Substantially non-aqueous foamable petrolatum based  pharmaceutical and cosmetic compositions and their uses

ABSTRACT

The present invention relates to stable substantially non-aqueous, non-alcoholic, non-silicone, foamable carrier compositions comprising petrolatum or mixtures thereof, at least one foam agent, at least one propellant, and with and without the addition of an active agent. The formulations may contain a solvent substantially miscible therein. The present invention further provides a method of treating, alleviating or preventing a disorder of mammalian subject in need thereof, comprising administering the above-mentioned compositions to an afflicted target site of said mammalian subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119(e)to co-pending U.S. Provisional Application No. 60/899,176 filed Feb. 2,2007, entitled “Non-Alcoholic Foamable Petrolatum Based PharmaceuticalAnd Cosmetic Compositions And Their Uses”, which is incorporated in itsentirety by reference

This application claims the benefit of priority under 35 U.S.C. §119(e)to co-pending U.S. Provisional Application No. 60/915,859 filed May 3,2007, entitled “Non-Aqueous Foamable Petrolatum And Miscible SolventBased Pharmaceutical And Cosmetic Compositions And Their Uses”, which isincorporated in its entirety by reference.

This application is a continuation-in-part of co-pending U.S. patentapplication Ser. No. 11/940,290, filed on Nov. 14, 2007, which claimsthe benefit of priority under 35 U.S.C. §119(e) to U.S. ProvisionalPatent Application No. 60/858,747, filed on Nov. 14, 2006, both entitled“Stable Non-Alcoholic Foamable Pharmaceutical Emulsion Compositions WithAn Unctuous Emollient And Their Uses”, and both herein incorporated intheir entirety by reference.

BACKGROUND

Petrolatum is used in dermatology to lubricate, protect, heal andmedicate the skin and as a vehicle for topical drugs. Petrolatum is notsuited to formation of foams. It is an unctuous solid and does not flowand is not shakable per se. Addition of large amounts of propellant totry and improve its flow is not desirable in general since the resultantmaterial can have a cooling effect on application to the skin, mucosalcavity or body cavity. Addition of hydrophobic solvents can be useful toimprove healing qualities of the formulation and to soften thepetrolatum, but it can also significantly and substantially complicateor impede foam formation.

Foams are complex multi-ingredient systems which do not form under allcircumstances. High quality foams are not at all easy to produceespecially in a waterless environment. Yet, foams are easy to apply, useand spread and are a preferred mode of topical application. Changes infoam composition, such as, by the addition of active ingredients, maydestabilize the foam. There is, therefore, a need for a foamcomposition, which provides desirable properties to the skin or bodycavity and can be stable whilst accommodating a variety of activeingredients.

Petrolatum in its various forms has a number of useful attributes foruse in topical foamable pharmaceutical and cosmetic compositions. Theyare inherently stable and inert, which are clearly desirablecharacteristics. They are also able to moisturize and soften the skinand in appropriate amounts can act as a protective or barrier layer andcan form a barrier to water, which can, for example, solubilize or causedestabilization of some active ingredients. By careful design andappropriate formulation of petrolatum compositions they can act toimprove drug delivery to the skin; provide a protective environment forthe drug and yet remain resistant to being washed off unintentially. Onthe other hand petrolatums are by their nature greasy materials and canpresent a difficult challenge to formulate them into a topicalnon-aqueous or substantially so foamable composition that can deliversubstantially uniform and stable foam that ameliorates and or overcomesthe look and feel of a greasy material. It is further a problem toincorporate into such a vehicle pharmaceutically effective amounts ofone or more active pharmaceutical ingredients such that they areuniformly present throughout the formulation and are effectivelydelivered especially without the use of an alcohol in the formulation.

Aliphatic alcohols in foam compositions promote fast drying and therebyattempt to address the sticky feeling left by many topical formulationsafter application; however, alcohols, and in particular short chainalcohols like methyl, ethyl and isopropyl alcohols are defatting agentsand may cause skin to become dry and cracked. Also, the presence of suchalcohols generates alcoholic foam that is thermal sensitive and quickbreaking, e.g., it collapses readily upon contact with a surface uponexposure to body temperature environment. Although certain compositionsbased on petrolatum are known they are, for example, designed to form anocclusive layer in the presence of active pharmaceutical agents that arenot soluble in the water or oil phase. Although some lipophilliccompositions containing petrolatum and silicone oil are known, thesilicone oil is an essential and main component and it is used to tryand overcome the greasy feeling of petrolatum. Silicones can havesubstantial disadvantages in foamable compositions and foams especiallyin significant levels.

In the light of the unctuous, greasy, tacky, and heavy nature ofpetrolatum, there are problems in producing stable emulsion foams ofgood quality and texture from high levels of petrolatum and there is areal technical challenge of achieving inter alia a good bubblestructure, texture, spreadability and look and feel. The presence ofwater is important in contributing to feel of the foam. Developing foamswith such characteristics that are substantially free of water is atechnical and inventive challenge. This challenge is increased where theformulations are to be substantially free of silicone oil andsubstantially free of lower alcohols.

Alcohol is known to impair the integrity of the skin barrier, dry theskin and cause skin irritation. The incidence skin irritation (burning,itching and stinging) can be very high. Thus, while alcohol is useful insolubilizing an active agent and enabling effective dermal penetrationof an active agent, the development of a safe foam vehicle, which willovercome the evident skin drying and irritation caused by alcohol, iswarranted, especially where sensitive skin, mucosa, or body cavitymembranes are being targeted. Furthermore, foam compositions thatpossess a lesser degree of thermal sensitivity, thus being more usefulfor the treatment of large skin areas are desired.

Foamable compositions that produce foams, which are soft are desirableespecially with improved stability.

It is particularly advantageous to have a foamable vehicle that issuitable for use as a base for delivery of not merely one type of activepharmaceutical ingredient (API) but is adaptable for use with one ormore API's from a wide range of different types of API's with relativelyminimal or minor adjustment to the vehicle. For example, by altering theamount of a component or by the addition of a buffer that provides a pHat which the API is stable as would be appreciated by a person skilledin the art.

SUMMARY

This application relates to petrolatum-based foamable vehicles,pharmaceutical compositions and resultant foams. In one embodiment, thepetrolatum-based foamable vehicles, pharmaceutical compositions andresultant foams are non-aqueous. In one embodiment, petrolatum-basedfoamable vehicles, pharmaceutical compositions and resultant foams havelow water content. The application further relates to such compositionsand to such resultant foams that are non-silicone and or arenon-alcoholic or substantially so.

A prime concept covered herein is that petrolatum as a hydrophobiccarrier is a main ingredient and is at least about 50% of the foamablecarrier alone or in combination with a solvent substantially miscibletherein for example a hydrophobic oil. In a preferred aspect thepercentage of petrolatum is more than about 60%. In one aspect thefoamable carrier is non-aqueous and the petrolatum is at least about 25%and is in combination with a solvent substantially miscible therein suchthat together they are at least about 80% and the carrier issubstantially free of silicone oil. By substantially free it is meantthat the silicone oil content in the composition is less than about 1%.In another aspect the foamable carrier is substantially non-aqueous orhas low water content and the petrolatum is more than about 50% or morethan about 55% and preferably more than about 60%. By substantiallynon-aqueous or low water content it is meant that the amount of water ifpresent in the composition is small and is less than about 26%,preferably less than about 16% and more preferably less than about 13%.Although the proportion of water is relatively very small by selectiveuse of appropriate and compatible surfactants it can be possible toproduce both water in oil and also oil in water petrolatum emulsioncompositions. Whilst these carriers are intended to be without lower orshort chain alcohols, where an API is provided as an alcoholic extract,such small amount of alcohol is permitted in the compositions. Incertain embodiments, such lower alcohol content is reduced oressentially eliminated by evaporation upon warming.

In an embodiment the petrolatum based carriers comprise one or moreactive pharmaceutical ingredients (API's). The formulations are designedto carry homogeneously large ranges of API's from microgram levels to upto about 33% of the composition. Some API's are stable in one kind ofenvironment whilst others require a different environment. For example,many steroids are known to undergo rearrangement at high pH, and aremore stable in acidic formulations whilst vitamin D and its derivativesfare better in a basic medium. So adding an acidic modulating agent suchas an acidic buffer, or fatty acid helps prevent steroid degradationwhilst the addition of a basic modulating agent, such as a basic bufferor triethanolamine is useful to maintain acceptable stability forvitamin D and derivatives. Other substances break down or react morerapidly in the presence of water and therefore are sustained better in anon-aqueous medium. The formulations described herein offer waterlessand substantially waterless or low water content variations and anappropriate carrier may be selected for an API depending on itssensitivity and reactivity in the presence and absence of relativelysmall amounts of water. Whilst the carrier compositions described hereinmay be useful carriers for API's some are not compatible in the sameformulations and may react or breakdown. The formulations described aresuitable for use in dual or multi chamber foam delivery devices, whereeach chamber delivers an API which if stored with the API's in the otherchamber(s) would have broken down. In one embodiment the carrier in thefirst chamber is substantially waterless and the carrier in the secondchamber is waterless. In another embodiment the carrier is basically thesame in each chamber although some minor variations such as to pH orartificial pH or in the presence of one or more preservatives,stabilizers, antioxidants, and the like may be made to reflect thespecific requirements of the API.

To generate the good quality foams described herein the formulationscontain a foam agent. In one or more embodiments the foam agent isselected from the group consisting of a surfactant, a surfactantcombination, a foam adjuvant and combinations thereof. In one or morefurther embodiments the quality may be improved by addition of apolymeric agent. The polymeric agent may preferably have somesurfactant-like properties or help to ameliorate the tacky greasyproperties of petrolatum.

In one embodiment, the foamable composition is a non-aqueous,non-alcoholic foamable composition that includes a foamable carrier andat least one liquefied or compressed gas propellant. The foamablecarrier includes (1) a petrolatum or mixtures thereof at a concentrationof about 25% to about 95% by weight; (2) a solvent substantiallymiscible in the petrolatum at a concentration of about 0% to about 70%by weight; and (3) at least one foam agent selected from the groupconsisting of a surfactant, a surfactant system, a foam adjuvant andcombinations thereof; at a concentration of about 0.1% to about 20% byweight. In the absence of the solvent, the petrolatum is present in thefoamable carrier at a concentration of at least about 50% by weight. Inthe presence of the solvent, (i) the petrolatum is present in thefoamable carrier at a concentration of at least about 25% by weight andthe solvent and petrolatum are together present in the foamable carrierat a concentration of least about 55% by weight; or (ii) the amount ofpetrolatum is about the same as or in excess of the solvent and,together, the solvent and petrolatum are present in the foamable carrierat a concentration of at least about 80%. The ratio of the foamablecarrier to the propellant is 100:10 to 100:35. The composition issubstantially free of silicone. The composition is stored in apressurized container or aerosol container and upon release expands toform a breakable foam.

In one embodiment, the foamable composition is a non-aqueous,non-alcoholic foamable composition that includes a foamable carrier andat least one liquefied or compressed gas propellant. The foamablecarrier includes (1) a petrolatum or mixtures thereof at a concentrationof about 50% to about 95% by weight; (2) a solvent substantiallymiscible in the petrolatum at a concentration of about 0% to about 45%by weight; (3) at least one foam agent selected from the groupconsisting of a surfactant, a surfactant system; a foam adjuvant andcombinations thereof at a concentration of about 0.1% to about 20% byweight; and (4) an effective amount of an active pharmaceutical agent.The ratio of the foamable carrier to the propellant ranges from about100:10 to about 100:35. The composition is substantially free ofsilicone. Moreover, the composition is resistant to centrifugation at1000 rpm for about 10 minutes; is flowable or flowable to a degree andor is shakable or substantially so when stored in a pressurizedcontainer or an aerosol container and upon release expands to form abreakable foam having no substantial or sustained cooling affect andhaving a foam hardness in the range of about 5 g to about 100 g.

In one embodiment, the foamable composition is a low water content,non-alcoholic foamable composition that includes a foamable carrier andat least one liquefied or compressed gas propellant. The foamablecarrier includes (1) a petrolatum or mixtures thereof at a concentrationof about 25% to about 95% by weight; (2) a solvent substantiallymiscible in the petrolatum at a concentration of 0% to about 70% byweight; (3) at least one foam agent selected from the group consistingof a surfactant, a surfactant system, a foam adjuvant and combinationsthereof; at a concentration of about 0.1% to about 20% by weight; and(4) water at a concentration of up to about 26% by weight. In theabsence of the solvent, the petrolatum is present in the foamablecarrier at a concentration of at least about 50% by weight. In thepresence of the solvent: (i) the petrolatum is present in the foamablecarrier at a concentration of at least about 25% by weight and thesolvent and petrolatum are together present in the foamable carrier at aconcentration of least about 55% by weight; or (ii) the amount ofpetrolatum is about the same as or in excess of the solvent and,together, the solvent and petrolatum are present in the foamable carrierat a concentration of at least about 80%. The ratio of the foamablecarrier to the propellant ranges from about 100:10 to about 100:35. Thecomposition is substantially free of silicone. The composition is storedin a pressurized container or aerosol container and upon release expandsto form a breakable foam. In one embodiment, the foamable composition isa low water content, non-alcoholic foamable composition that includes afoamable carrier and at least one liquefied or compressed gaspropellant. The foamable carrier includes (1) a petrolatum or mixturesthereof at a concentration of about 50% to about 95% by weight; (2) asolvent substantially miscible in the petrolatum at a concentration ofabout 0% to about 45% by weight; (3) at least one foam agent selectedfrom the group consisting of a surfactant, a surfactant system; a foamadjuvant and combinations thereof at a concentration of about 0.1% toabout 20% by weight; and (4) an effective amount of an activepharmaceutical agent. The solvent is water and is present in the carrierat a concentration of about 0.1% to about 26% by weight. The ratio ofthe foamable carrier to the propellant ranges from about 100:10 to about100:35. The composition is substantially free of silicone. Thecomposition is resistant to centrifugation at 1000 rpm for about 10minutes and is flowable or flowable to a degree and or is shakable orsubstantially so when stored in a pressurized container or aerosolcontainer and upon release expands to form a breakable foam having nosubstantial or sustained cooling affect and having a foam hardness inthe range of about 5 g to about 100 g

In one or more embodiments there is provided a substantiallynon-aqueous, non-alcoholic, non-silicone foamable carrier compositioncomprising:

-   (1) a petrolatum or mixtures thereof at a concentration of about 25%    to about 95% by weight prior to the addition of propellant;-   (2) a solvent substantially miscible therein other than the    propellant, at a concentration of about 0% to about 70% by weight    prior to the addition of propellant;-   (3) at least one foam agent selected from the group consisting of a    surfactant, surfactant system, a foam adjuvant and combinations    thereof at a concentration of about 0.1% to about 20% by weight    prior to the addition of propellant;-   (4) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   wherein in the absence of the said substantially miscible solvent    the amount of petrolatum is at least about 50%; and-   wherein in the presence of the substantially miscible solvent the    amount of petrolatum is either (i) at least about 25% prior to the    addition of propellant and the amount of the substantially miscible    solvent in combination with petrolatum is at least about 55% prior    to the addition of propellant or (ii) the amount of petrolatum is    about the same as or in excess of the substantially miscible solvent    and their combined amount is at least about 80% prior to the    addition of propellant and wherein the composition is stored in an    aerosol container and upon release expands to form a breakable foam.

In one or more other embodiments the amount of petrolatum is in excessof about 50% and there is present an amount of solvent substantiallymiscible therein between about 0.1% to about 45%. Preferably it is inexcess of about 55% and the range is about 0.1% to about 40% and morepreferably in excess of about 60% and the range is about 0.1% to about35%.

In one or more embodiments there is provided a substantiallynon-aqueous, non-alcoholic non-silicone foamable carrier compositioncomprising:

-   (1) a petrolatum or mixtures thereof at a concentration of about 50%    to about 95% by weight prior to the addition of propellant;-   (2) a solvent substantially miscible therein other than the    propellant, at a concentration of about 0% to about 45% by weight    prior to the addition of propellant;-   (3) at least one foam agent selected from the group consisting of a    surfactant, a surfactant system; a foam adjuvant and combinations    thereof at a concentration of about 0.1% to about 20% by weight    prior to the addition of propellant;-   (4) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and-   (5) an effective amount of an active pharmaceutical agent; and    wherein the composition is resistant to centrifugation at 1000 rpm    for about 10 minutes; wherein the composition is flowable or    flowable to a degree and or is shakable or substantially so when    stored in an aerosol container and upon release expands to form a    breakable foam having no substantial or sustained cooling affect and    having a foam hardness in the range of about 5 g to about 100 g.

In one or more other embodiments the formulations and foams arenon-aqueous, non-silicone and non-alcoholic (being in the absence of alower alcohol). In one or more other embodiments the formulations andfoams have at least two of the three features listed.

Non-Aqueous Formulations

Foamable non-aqueous compositions are described that are non-aqueous oressentially so, are stable and able to provide some of the mainattributes of a petrolatum ointment or cream in a topical foamableformulation and which can deliver a substantially uniform and stablefoam without the use of an alcohol in the formulation. By “non-aqueous”or “essentially non-aqueous” it is meant that the compositions containat most incidental and trace amounts of water. In one embodiment, thewater content is very small being about less than about 5%. By “withoutalcohol” or “non-alcoholic” it is intended to exclude the use of loweror short chain alcohols. These compositions comprise petrolatum. Thepetrolatum phase is the main phase or is a major element of the carrier.The formulations can also ameliorate or overcome to a degree the lookand feel of a greasy material. These compositions can provide animproved delivery system over ointments and creams.

In one or more embodiments, the foamable non-aqueous compositions areflowable or flowable to a degree and or are shakable and can expand toproduce a good quality foam without the propellant having a significantcooling effect.

In one or more embodiments, the foamable non-aqueous compositionsproduce foams that are soft or with an improved softness.

In one or more embodiments, pharmaceutically effective amounts of one ormore active pharmaceutical ingredients are incorporated into thefoamable non-aqueous composition.

In one or more embodiments an active ingredient is distributedhomogeneously in the composition are described.

In one or more embodiments, substantial amounts of an active ingredientare distributed homogeneously in the composition.

In one or more embodiments, foamable non-aqueous compositions areprovided without a co-solvent.

In one or more embodiments, foamable non-aqueous compositions areprovided in which the solvent comprises a propellant, which evaporateson expansion to produce a foam.

In one or more embodiments, the foamable non-aqueous composition issuitable for use as a base for delivery for API's, which are by theirnature emulsion destabilizers, micelle destabilizers or interphasedestabilizers, with relatively minimal or minor adjustment to thevehicle or in the method of preparation. Pharmaceutical salts, forexample, are in general emulsion destabilizers.

The foamable non-aqueous compositions are described that improve thesolubility and/or deliverability of the active pharmaceutical to atarget skin, mucosa or body cavity area and/or provide an improveddelivery system over ointments and creams.

The present invention relates to non-aqueous, non-alcoholic,non-silicone, foamable carriers and pharmaceutical and cosmeticcompositions comprising at least, a hydrophilic carrier comprisingpetrolatum or mixtures thereof with a solvent substantially miscibletherein, a surfactant, and a propellant with and without the addition ofan active agent.

The present invention relates to non-aqueous, non-alcoholic,non-silicone, foamable carriers and pharmaceutical and cosmeticcompositions comprising at least, a hydrophilic carrier comprisingpetrolatum or mixtures thereof with a solvent substantially miscibletherein, a surfactant, and a propellant, with and without the additionof an active agent, wherein the foam produced by the carrier orpharmaceutical composition when packaged in an aerosol container andreleased has a foam hardness in the range of about 5 g to about 100 g.Preferably, hardness level is towards the lower part of the rangereflecting relative softness. Further, in an embodiment when theresultant foam is applied to a surface it does not have any cooling orsignificant cooling effect.

The present invention relates to non-aqueous, non-alcoholic,non-silicone foamable carriers and pharmaceutical and cosmeticcompositions comprising a petrolatum or mixtures thereof with a solventsubstantially miscible therein, a surfactant, and a propellant, whichcan hold substantial amounts of active agents and still produce a goodquality stable breakable foam.

The present invention relates to non-aqueous, non-alcoholic,non-silicone foamable carriers and pharmaceutical and cosmeticcompositions with relatively high viscosity prior to addition of thepropellant. In some embodiments, relatively high viscosity is aviscosity from about 12,000 CPs to about 500,000 CPs. In someembodiments, relatively high viscosity is a viscosity from about 20,000CPs to about 500,000 CPs. In some embodiments, relatively high viscosityis a viscosity from about 50,000 CPs to about 500,000 CPs. In someembodiments, relatively high viscosity is a viscosity from about 100,000CPs to about 500,000 CPs. In some embodiments, relatively high viscosityis a viscosity of at least about 20,000 CPs. In some embodiments,relatively high viscosity is a viscosity of at least about 50,000 CPs.In some embodiments, relatively high viscosity is a viscosity of atleast about 100,000 CPs.

The present invention also relates to non-aqueous, non-alcoholic,non-silicone, foamable carriers and pharmaceutical and compositionscomprising a petrolatum or mixtures thereof with a solvent substantiallymiscible therein, a surfactant, a propellant, wherein the propellantdissolves in the composition.

The present invention also relates to non-aqueous, non-alcoholic,non-silicone, foamable carriers and pharmaceutical and cosmeticcompositions comprising a petrolatum or mixtures thereof with a solventsubstantially miscible therein, a surfactant, a propellant, wherein thepropellant dissolves in the composition and which when stored in apressurized canister rapidly expands on release to produce a breakablefoam.

The present invention also relates to non-aqueous, non-alcoholic,non-silicone, foamable carriers and pharmaceutical and cosmeticcompositions comprising a petrolatum or mixtures thereof with a solventsubstantially miscible therein, a surfactant, a propellant, wherein thepropellant dissolves in the composition.

The present invention also relates to non-aqueous, non-alcoholic,non-silicone, foamable based pharmaceutical compositions comprisingpetrolatum with a solvent substantially miscible therein, a surfactant,a propellant, and an active agent wherein the active agent is insolubleand is distributed uniformly in the composition or, wherein thecomposition or a phase thereof is able at least to a very limited degreeto solubilize the active agent or wherein the composition or a phase ofthe composition is able to a degree to solubalize the active agent.

In certain embodiments where the composition is essentially non-aqueousbut contains a small amount of water the hydrophobic carrier orcomposition does not in certain aspects contain a non-propellant organicco-solvent.

The present invention relates to non-aqueous, non-alcoholic,non-silicone, foamable compositions wherein each composition is flowableor flowable to a degree and or is shakable or substantially shakablewhen stored in an aerosol container and upon release expands to form abreakable foam that effectively delivers petrolatum with a solventsubstantially miscible therein, at a concentration of from about 25% toabout 95% by weight of the foam. Preferably the amount of petrolatum isabout more than about 35% and more preferably the amount of petrolatumis more than about 50% or more than about 55% or more than about 60%.

The present invention relates to a non-aqueous, non-alcoholic,non-silicone, foamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof with a solvent substantially    miscible therein, at a concentration of about 25% to about 95% by    weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system, at a concentration    of about 0.1% to about 20% by weight; prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition; and wherein the composition is stored in an aerosol    container and upon release expands to form a breakable foam.

In one or more embodiments the solvent substantially miscible inpetrolatum is from about 1% to about not more than 68% by weight of thecomposition, preferably about not more than 55%, more preferably aboutnot more than 45% by weight of the composition.

The present invention further relates to said compositions additionallycomprising one or more additional active agents.

Thus, the present invention also relates to a non-aqueous,non-alcoholic, non-silicone, foamable pharmaceutical or cosmeticcomposition comprising:

-   (1) a petrolatum or mixtures thereof with a solvent substantially    miscible therein, at a concentration of about 25% to about 95% by    weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 20% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) at least one foam adjuvant; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the wherein the composition is flowable or flowable to a    degree and or is shakable or substantially so when stored in an    aerosol container and upon release expands to form a breakable foam.

In one or more embodiments the solvent substantially miscible inpetrolatum or mixtures thereof is a hydrophobic solvent or an unctuousadditive.

In a particular embodiment the solvent is an oil, preferably atherapeutically active oil. Thus, the present invention relates to saidcomposition comprising one or more therapeutically active oils. Thepresence of oil on the one hand acts to soften and increase the fluidityof the petrolatum or mixtures thereof but on the other hand itsignificantly and substantially complicates the formulation and theselection of surfactants and other solvents and or foam adjuvants and orpropellants appropriate to achieve a foam of quality.

In an embodiment the solvent comprises a mineral oil. In otherembodiments the solvent comprises a therapeutic oil.

In an embodiment, the gas propellant and its amount can be significantin improving the characteristics of the foam. Indeed the propellant mayitself be a solvent with respect to the foamable composition even thoughultimately the propellant disappears from the composition upon releaseas it expands to form a breakable foam.

In an embodiment, the gas propellant comprises n butane.

In an embodiment, the gas propellant comprises a mixture of n-butane,isobutane and propane. The mixture may be varied as a man skilled in theart would appreciate.

In some embodiments, the foamable cosmetic or pharmaceutical compositionis non-flammable, wherein said gas propellant containshydrofluorocarbon.

Low Water Content Formulations

The aforesaid description of the non-aqueous formulations is alsogenerally applicable to the low water content or substantiallynon-aqueous formulations herein with where necessary appropriate changesas would be appreciated by a man of the art. For example, wherewaterless is mentioned above the compositions further described belowmay also be waterless but without substantial amounts of a hydrophobicoil or where the compositions described below contain some small amountof water the compositions are formulated as an emulsion as opposed to asingle phase. Similarly, where compositions above refer to a solventwhich is substantially miscible in petrolatum, the compositions beloware primarily concerned with hydrophilic or polar solvents. Thus, theprevious section may be read and applied to these formulations withthese points in mind. Other embodiments by way of example arespecifically described below.

Petrolatum foamable compositions wherein the petrolatum phase is themain phase of the composition that are shakable and can expand toproduce a good quality foam without the propellant having a significantcooling effect are described and can provide an improved delivery systemover ointments and creams.

Petrolatum foamable and non-aqueous petrolatum foamable compositions inwhich the petrolatum phase is the main phase of the composition andcontains an active ingredient distributed homogeneously in thecomposition are described. These compositions provide an improveddelivery system over ointments and creams.

In one or more embodiments, petrolatum foamable compositions areprovided without a cosolvent in which the petrolatum phase is the mainphase of the composition and contains substantial amounts of an activeingredient distributed homogeneously in the composition.

In one or more embodiments, petrolatum foamable compositions areprovided in which the solvent is a propellant, which evaporates onexpansion to produce a foam. The petrolatum phase is the main phase ofthe composition and can contain substantial amounts of an activeingredient distributed homogeneously in the composition.

In one or more embodiments, a foamable petrolatum composition issuitable for use as a base for delivery of not merely one type of APIbut is adaptable for use with one or more API's from a wide range ofdifferent types of API's with relatively minimal or minor adjustment tothe vehicle. For example, by altering the amount of a component or bythe addition of a buffer that provides a pH at which the API is stableas would be appreciated by a person skilled in the art.

The present invention also relates to stable non-alcoholic foamablepetrolatum based carriers and pharmaceutical and cosmetic compositionscomprising a petrolatum or mixtures thereof, a surfactant, a propellant,with and without a solvent wherein the propellant dissolves in thecomposition and which when stored in a pressurized canister rapidlyexpands on release to produce a breakable foam.

The present invention also relates to stable non-alcoholic foamablepetrolatum based carriers and pharmaceutical and cosmetic compositionscomprising a petrolatum or mixtures thereof, a surfactant, a propellant,with and without a solvent wherein the propellant dissolves in thecomposition and which are resistant to creaming at 3000 rpm for at least10 minutes.

The present invention also relates to stable non-alcoholic foamablepetrolatum based pharmaceutical and cosmetic compositions comprisingpetrolatum mixtures.

The present invention also relates to stable non-alcoholic foamablepetrolatum based pharmaceutical compositions comprising petrolatum, asurfactant, a solvent, a propellant, and an active agent wherein theactive agent is insoluble and is distributed uniformly in thecomposition which does not contain a non propellant organic cosolvent.

The present invention also relates to stable non-alcoholic foamablepharmaceutical emulsion compositions comprising petrolatum, asurfactant, a solvent, a propellant, and an active agent, wherein thecomposition or a phase thereof is able at least to a very limited degreeto solubilize the active agent; and or so that the composition does notcomprise a non propellant organic cosolvent.

The present invention also relates to stable non-alcoholic foamablepetrolatum based pharmaceutical compositions comprising a petrolatum ormixtures thereof, a surfactant, a solvent, a propellant, and an activeagent wherein the composition or a phase of the composition is able to adegree to solubalize the active agent.

The present invention relates to stable non-alcoholic foamablepetrolatum based compositions wherein each composition is shakable orsubstantially shakable stored in an aerosol container and upon releaseexpands to form a breakable foam that effectively delivers petrolatum ata concentration of about 50% to about 95% by weight of the foam.Preferably petrolatum is delivered at a concentration of at least about55%, and more preferably at least about 60%.

The present invention relates to stable non-alcoholic foamablepetrolatum based compositions wherein each composition is flowable orflowable to a degree when stored in an aerosol container and uponrelease expands to form a breakable foam that effectively deliverspetrolatum at a concentration of about 50% to about 95% by weight of thefoam.

The present invention relates to a stable non-alcoholic foamable carriercomposition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight; prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is stored in an aerosol    container and upon release expands to form a breakable foam.

The present invention further relates to said compositions comprising inaddition a solvent, preferably water or a hydrophilic solvent. In one ormore embodiments the solvent is about not more than 40% by weight of thecomposition.

The present invention relates to a stable non-alcoholic foamablepharmaceutical or cosmetic composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) at least one solvent; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is flowable or flowable    to a degree when stored in an aerosol container and upon release    expands to form a breakable foam. In an alternative embodiment the    carrier composition is shakable or substantially so.

The present invention further relates to said composition comprising oneor more additional therapeutically active oils.

In an embodiment the active agent is an alcoholic extract, an aqueousextract or an aqueous alcoholic extract. In such limited circumstancesthe amount of water or lower alcohol is permitted to the extentnecessary to deliver an effective amount of the API.

In an embodiment these substantially non-aqueous formulations and foamsare also non-silicone and or non-alcoholic or substantially so.

Methods of Treatment Using Non-aqueous and Substantially Non-AqueousCompositions

The present invention further provides a method of treating, alleviatingor preventing a disorder of mammalian subject, comprising administeringa therapeutically effective amount of the herein-mentioned compositionsto an afflicted target site.

The present invention further provides a method of treating, alleviatingor preventing a nappy rash of mammalian subject, comprisingadministering a therapeutically effective amount of the herein-mentionedcompositions to an afflicted target site. In an embodiment thepetrolatum based composition contains Zinc Oxide as an API for useagainst or to treat or prevent minor skin irritations (e.g., burns,cuts, poison ivy, rash, particularly diaper or nappy rash). Thecompositions described herein are ideal for carrying effective highconcentrations of API.

The present invention further provides a use of any of theherein-mentioned compositions for the manufacture of a medicament fortreating, alleviating or preventing a disorder of a mammalian subject inneed thereof.

The present invention further provides a use of any of theherein-mentioned compositions for the manufacture of a medicament fortreating, alleviating or preventing nappy rash of a mammalian subject inneed thereof.

In one or more embodiments any of the foregoing methods of treatment maybe applied by providing a first pharmaceutical composition in a firstfoam canister and a second pharmaceutical composition in a secondcanister. The contents of each canister may be applied individually inan appropriate sequence or at the same time. The canisters may be partof a dual or multi chamber foam delivery device.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1 a and 1 b are pictures of two elevations (vertical andhorizontal) of a waterless oil relatively low petrolatum carriercomposition with Aluminum starch octenyl succinate (“ASOS”) comprising apropellant, which shows that the formulation is homogeneous and liquid.The formulation is presented in Example 1.

FIGS. 2 a and 1 b are pictures of two elevations (vertical andhorizontal) of a waterless carrier high petrolatum oil carriercomposition comprising a propellant, which shows that the formulation ishomogeneous and liquid. The formulation is presented in Example 2.

FIG. 3 is a picture of a waterless carrier composition comprising apropellant, which shows that the propellant is dissolved in thepetrolatum of the composition and appears as a single translucent phase.

DETAILED DESCRIPTION Non-Aqueous Formulations

The present invention provides safe and effective foamable petrolatumbased pharmaceutical and cosmetic vehicles and compositions. Moreparticularly, it provides non-aqueous, non-alcoholic, non-silicone oressentially so, foamable petrolatum based pharmaceutical or cosmeticcarriers and compositions in which a petrolatum or mixtures thereof isthe largest single component or is a substantial or major component byweight in the carrier or composition. The present invention furtherprovides low water content foamable petrolatum based pharmaceutical orcosmetic carriers in which a petrolatum or mixture thereof is thelargest single component or is a substantial or major component byweight in the carrier or composition. The vehicle or composition furthercomprises at least one surfactant or surfactant system. The vehicle orcomposition further comprises at least one propellant wherein thecomposition is stored in an aerosol container and upon release expandsto form a foam. In one or more embodiments the carrier or compositionfurther comprises one or more active agents which may be insoluble, atleast soluble to a very limited degree or soluble in the composition ora phase thereof.

By low water content or essentially non-aqueous it is intended theformulations may have present a small amount of water (i.e., incidentalor trace amounts of water). In one embodiment, the formulations haveless than about 5% water content. In one embodiment, the formulationshave less than about 4% water content. In one embodiment, theformulations have less than about 3% water content. In one embodiment,the formulations have less than about 2% water content. In oneembodiment, the formulations have less than about 1% water content. Inone or more embodiments where the composition is has low water contentor is essentially non-aqueous it may contain a small amount of water andin certain aspects the carrier or composition does not contain a nonpropellant organic co-solvent.

It was unexpectedly discovered that after dissolving the propellant intopre-foam formulations without solvent so that the viscosity is high thata change in the petrolatum formulation is observed such that it isshakable and flowable. It is believed that in certain embodiments somecompositions may be marginally or apparently non-shakable and still havea degree of flowability such that a good quality foam can be expelledfrom the canister.

The present invention also relates to foamable petrolatum basedpharmaceutical and cosmetic compositions comprising petrolatum mixtures.By combining appropriate amounts of different types of petrolatum with asolvent substantially miscible therein it is possible for example, toprepare foams which are able to mimic substantially barrier propertiesof petrolatum ointments and petrolatum based barrier creams for nappyrash. In one embodiment a low melting point petrolatum is mixed with apetrolatum with a higher melting point. In certain embodiments the majorpetrolatum is the lower molecular weight petrolatum. In otherembodiments the petrolatum is mixed in a ratio for example, of about5:1; 4:1; 3:1; 2:1; or 1:1 of lower melting point to higher meltingpoint petrolatum. In some embodiments the ratio of mixture can be ofhigher melting point to lower melting point. In certain embodiments asofter type of petrolatum is utilized on its own or in a mixture.

In an embodiment it was surprisingly found that it was possible toexclude stabilizers other than a surfactant and still prepare areasonable foam in the presence of ASOS, which whilst improving skinfeel can ameliorate foam quality

In one or more embodiments it is possible to incorporate uniformly intoa petrolatum based foamable vehicle, pharmaceutically or cosmeticallyeffective amounts of one or more active cosmetic, therapeutic orpharmaceutical ingredients (agents).

In one or more embodiments it is possible to incorporate uniformly intoa petrolatum based foamable vehicle, substantial amounts of one or moreactive ingredients.

In one or more embodiments it is possible to deliver uniformly in a foamproduced from a petrolatum based foamable vehicle, an amount of activeingredients of up to about 33% preferably up to 20% by weight of thecomposition before addition of propellant.

In one or more embodiments, the foamable carriers described herein aresuitable for use as a base for delivery of not merely one type of APIbut are adaptable for use with one or more API's from a wide range ofdifferent types of API's with relatively minimal or minor adjustment tothe carrier, for example, by altering the amount of a component, aswould be appreciated by a person skilled in the art. Although pH appliesto aqueous environments in one or more embodiments the presence of abuffer or pH agent can also help to provide a stable environment for anactive agent. In a preferred aspect the buffer or pH agent is providedin an effective amount that provides a pH at which the API is stable.Likewise chelating agents, antioxidants and anti-ionization agents mayalso be usefully added

In one or more embodiments there is provided a foamable vehicle orcarrier that is suitable for use as a base for delivery for API's, whichare by their nature destabilizes, with relatively minimal or minoradjustment to the vehicle or in the method of preparation.Pharmaceuticals that have a hydrophobic region may be absorbed at leastpartially by the hydrophobic carrier compositions. Thus, theidentification of petrolatum based compositions that are effective inhaving anti destabilization properties in combination with at least onesurfactant or surfactant system provides special advantages and isanother embodiment.

In one or more embodiments there is provided a non-aqueous,non-alcoholic, non-silicone, foamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof with a solvent substantially    miscible therein, at a concentration of about 25% to about 95% by    weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 20% by weight; prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and wherein the composition is stored in an aerosol container and    upon release expands to form a breakable foam.

In certain embodiments the foamable carriers and compositions describedherein are resistant to centrifugation at 1000 rpm for at least 10minutes, for example, when the petrolatum concentration is relativelyhigh.

In one or more embodiments there is provided a non-aqueous,non-alcoholic, non-silicone, foamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof with a solvent substantially    miscible therein, at a concentration of about 20% to about 95% by    weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 20% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) at least one foam adjuvant; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the composition is flowable or flowable to a degree and    or is shakable or substantially so when stored in an aerosol    container and upon release expands to form a breakable foam having a    foam hardness in the range of about 5 g to about 100 g.

A breakable foam is thermally stable or substantially so, yet breaksunder sheer force. The breakable foam is not “quick breaking”, i.e., itdoes not readily collapse upon exposure to body temperature environment.Sheer-force breakability of the foam is clearly advantageous overthermally induced breakability, (due to, for example, the presence ofalcohol) since it allows comfortable application and well directedadministration to the target area.

‘Shakability’ in the context herein means that the composition containssome or sufficient flow to allow the composition to be mixed or remixedon shaking. By shakable it indicates that some motion or movement of theformulation can be sensed when the canister containing the formulationis shaken or is firmly shaken.

In one or more embodiments there is provided a non-aqueous,non-alcoholic, non-silicone, foamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof with a solvent substantially    miscible therein, at a concentration of about 50% to about 95% by    weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 20% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) at least one foam adjuvant; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the composition is resistant to centrifugation at 1000    rpm for at least 10 minutes; wherein the composition is flowable or    flowable to a degree and or is shakable or substantially so when    stored in an aerosol container and upon release expands to form a    breakable foam.

In one or more embodiments the foamable carriers and compositionsdescribed herein are stored in an aerosol container and upon releaseexpands to form a breakable foam having a foam hardness in the range ofabout 5 g to about 100 g.

In a further embodiment the foam hardness is in the range of about 10 gto about 90 g or more preferably about 15 g to about 55 g.

In a further embodiment the petrolatum or mixture thereof influencesfoam hardness such that the foam produced is soft. Softness especiallywith stability improves usability. If the foam, for example, is intendedupon application to form a barrier, the attribute of softness should beadjusted, balanced, increased or reduced with the need to provide aneffective barrier. A little less softness can be achieved, for example,by adding a proportion of petrolatum with a higher melting point orincreasing the amount of waxy or solid surfactant. Alternatively it maybe achieved by reducing the amount of solvent or liquid surfactant. Tothe extent liquid surfactant is reduced it may be compensated byincreasing solid or waxy surfactant or by addition of foam adjuvants.

In a further embodiment petrolatum or mixtures thereof is between about57% to about 90% by weight of the foamable carrier (i.e., prior to theaddition of propellant).

In a further embodiment petrolatum or mixtures thereof is preferablybetween about 57% to about 82% by weight of the foamable carrier.

In a further embodiment the surfactant or surfactant system ispreferably between about 3% to about 15% by weight of the foamablecarrier (i.e., prior to the addition of propellant).

The ratio between the petrolatum and solvent is determined according tothe desirable level of petrolatum and the importance of the solvent fromone or more non limiting aspects including, therapeutic effect,liquefying effect, hardness, resistance to centrifugation, enhancingsolubility or penetration, and taking into account appropriate anddesirable pharmacologic and safety properties of the product. Typically,the solvent to petrolatum ranges between about 3:1 and about 1:100, forexample, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about1:4, about 1:5 about, about 1:10; about 2:25, about 1:15, about 2:35,about 1:20, about 2:45 and about 1:25, about 1:30; about 1:40 about1:50; about 1:60; about 1:70; about 1:80; about 1:90; about 1:100preferably between about 1:15 to about 1:60.

In one or more embodiments the solvent is a PPG alkyl ether, preferablyPPG15 stearyl ether.

In one or more embodiments the solvent is a combination of an oil and aPPG alkyl ether. In a preferred embodiment the oil comprises a lightmineral oil and the ether comprises PPG15 stearyl ether.

In one or more embodiments the surfactant or combination of surfactantsis selected from one or more of the group consisting of ceteth20,steareth 2, steareth 20, glucose methyl stearate, methyl glucosesesquistearate, Span 20, Span 80, Tween 20, and Tween 80.

In one or more embodiments the combination of surfactants is a complexemulgator.

In one or more embodiments the foam adjuvant is selected from one ormore of the group consisting of oleyl alcohol, behenyl alcohol, andcetostearyl alcohol.

In one or more embodiments the foam adjuvant is selected from one ormore of the group consisting of cetyl alcohol, and stearyl alcohol.

In a further embodiment the surfactant and its amount is selected sothat the composition is sufficiently shakable so that substantiallyuniform foam extrusion is possible. In general terms, as the amount ofsolid or waxy surfactant is increased the shakability of the formulationreduces until a limitation point is reached where the formulationbecomes non shakable and unsuitable. To this extent the maximumeffective amount of surfactant that may be used may be limited by theneed for shakability.

In a further embodiment the surfactant and its amount is selected sothat the composition is sufficiently flowable so that substantiallyuniform foam extrusion is possible. In general terms, as the amount ofsolid or waxy surfactant is increased the flowability of the formulationreduces until a limitation point is reached where the formulationbecomes non flowable and unsuitable To this extent, the maximumeffective amount of surfactant that may be used may be limited by theneed for some flowability.

In selecting a suitable surfactant or combination thereof it should beborne in mind that in certain exceptional embodiments the compositionmay be marginally shakable or apparently non shakable but neverthelessis flowable or flowable to a degree that it can flow under the pressureof the propellant through an aerosol valve to expand and form a goodquality foam. This exception may be due to one or more of a number offactors such as, the high viscosity, the softness, the lack of crystals,the pseudoplastic or semi pseudo plastic nature of the composition andthe dissolution of the propellant into the petrolatum. In suchcircumstances apart from using a standard dip tube aerosol system incertain embodiments an inverse canister system without a dip tube may bepreferred and is ideal for formulations which are flowable to a degreebut are apparently or marginally non shakable.

In a further embodiment the propellant or mixtures thereof and amountsthereof are selected so that the composition is sufficiently shakable sothat substantially uniform foam extrusion is possible. An aspect of thisembodiment is the property of the propellant to form a single phase withpetrolatum.

In a further embodiment the propellant or mixtures thereof and amountsthereof are selected so that the composition is sufficiently flowable sothat substantially uniform foam extrusion is possible. An aspect of thisembodiment is the property of the propellant to form a single orhomogeneous phase with petrolatum.

In a further embodiment the propellant and the surfactant or surfactantsystem and their amounts are selected so that the composition issufficiently shakable so that substantially uniform foam extrusion ispossible.

In a further embodiment the propellant and the surfactant or surfactantsystem and their amounts are selected so that the composition issufficiently flowable so that substantially uniform foam extrusion ispossible.

In a further embodiment the propellant is preferably between about 5% toabout 30% by weight of the composition.

In a further embodiment the propellant is preferably between about 8% toabout 20% by weight of the composition.

In a further embodiment the propellant is in a sufficient amount toexpel the composition from the canister upon actuation to form a foambut is not sufficient to have a cooling effect on application of thefoam to the skin.

In a further embodiment the foam produced from the composition orcarrier is capable of remaining substantially unchanged after at leastone freeze thaw cycle.

In a further embodiment the degree of solubility of the active agent isslightly, sparingly or more soluble.

In a further embodiment the degree of solubility of the active agent isvery slightly soluble.

In certain embodiments where the composition has low water content or isessentially non-aqueous, the carrier or composition does not comprise anon propellant organic co-solvent.

In a further embodiment the active ingredient may be a cosmetic agent ora placebo. In which case, the carrier composition may itself be usefulfor the treatment prevention or amelioration of various general skin andcosmetic complaints such as aging, atopic dermatitis, contact dermatitisand radiation or burn injury and the like.

In one or more embodiments the composition further comprises one or moreadditional active agents. In a preferred embodiment the active agentscompliment each other or may have a synergistic effect.

In one or more embodiments comprises one or more additionaltherapeutically active oils.

In some embodiments, the foamable cosmetic or pharmaceutical compositionis non-flammable, wherein said gas propellant containshydrofluorocarbon.

In one or more embodiments there is provided a method of treating,alleviating or preventing a disorder of mammalian subject, comprisingadministering a therapeutically effective amount of the above-mentionedcompositions to an afflicted target site.

In one or more embodiments there is provided a method of treating,alleviating or preventing nappy rash in a mammalian subject, comprisingadministering a therapeutically effective amount of the above-mentionedcompositions to an afflicted target site.

In one or more embodiments there is provided use of a therapeuticallyeffective amount of the above-mentioned compositions in the manufactureof a medicament.

In one or more embodiments there is further provided a therapeuticallyeffective amount of the above-mentioned compositions for use in themanufacture of a medicament.

In one or more embodiments the petrolatum may alone or in combinationwith a stabilizing agent or vica versa may help to ameliorate,counteract, or overcome undesirable effects and drawbacks of an API,such as destabilization, precipitation or breakdown.

In one or more embodiments the stabilizing agent can also assist orimprove the skin feeling. Non limiting examples are polymeric agent suchas ASOS, an alkyl lactate such as C-12 to C-15 alkyl lactate, acellulose like carboxymethyl cellulose sodium and microcrystallinecellulose or methocel and xantham gum. In a preferred embodiment thepolymeric agent comprises ASOS.

Additionally, in one or more embodiments there is provided foamablepetrolatum based compositions that are stable and able to provide someof the main attributes of a petrolatum composition when delivered as atopical substantially uniform and stable foam and without the use of analcohol in the formulation.

Additionally, in one or more embodiments there is provided foamablepetrolatum based compositions that are stable and able to provide someof the main attributes of a petrolatum composition when delivered as atopical substantially uniform and stable foam with barrier propertiesand without the use of a volatile alcohol and or a volatile silicone inthe formulation. In an embodiment the barrier properties are enhanced orimproved by the refatting qualities of the solvent substantiallymiscible in the petrolatum.

In one or more embodiments a foamable pharmaceutical composition isprovided also incorporating an added hydrophobic solvent, for example,as a look and feel enhancer, solubility enhancer or deliverabilityenhancer.

In one or more embodiments a foamable pharmaceutical composition isprovided also incorporating an added polar solvent, for example, aspenetration enhancer, solubility enhancer or deliverability enhancer.Preferably the enhancer is selected to be substantially miscible in thecomposition. In one or more embodiments the polar solvent or the potentsolvent is in a small amount.

In one or more embodiments non limiting examples of other non-aqueoussolvents, which preferably are added in small amounts are solvents suchas polyethylene glycol (PEG), isosorbide derivatives, such as dimethylisosorbide, propylene gycol (PG), hexylene glycol and glycerin,diethylene glycol monoethyl ether, a liquid polyethylene glycol,glycofurol, tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO,a pyrrolidone, N-methylpyrrolidones, N-Methyl-2-pyrrolidone,1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-typesurfactant, an alpha hydroxy acid, lactic acid and glycolic acid,hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol(transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol,mannitol, oligosaccharides, monooleate of ethoxylated glycerides havingabout 8 to 10 ethylene oxide units, and cyclodextrins, esters, such asethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl butyrate, propylene glycolmonoacetate, propylene glycol diacetate, .epsilon.-caprolactone andisomers thereof, .delta.-valerolactone and isomers thereof,.beta.-butyrolactone and isomers thereof; and other solubilizers knownin the art, such as dimethyl acetamide.

In an embodiment the non-aqueous solvent is monooctanoin.

In one or more embodiments a foamable pharmaceutical composition isprovided wherein the ratios of surfactant, petrolatum and added polarsolvent as penetration enhancer are selected or adapted to provide aselected pharmacological or safety property.

In one or more embodiments a foamable pharmaceutical composition isprovided also incorporating a polymeric agent. The polymeric agentwhilst it is believed to be non essential can be useful in improvingfoam characteristics including hardness, viscosity, and feel.

In one or more embodiments the polymeric agent is selected from abioadhesive agent, a gelling agent, a film forming agent and a phasechange agent and can be from about 0.01% to about 5% by weight.

In one or more embodiments of the pharmaceutical or cosmetic foamableproduct is non-flammable.

According to one or more embodiments, the foamable composition isnon-alcoholic or alcohol free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butaneol, iso-butaneol, t-butaneol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. In one or more further embodiments, the composition issubstantially alcohol-free and can includes less than about 5% finalconcentration of lower alcohols, preferably less than about 2%, morepreferably less than about 1%. Where the active ingredient is providedin an alcoholic extract then in such limited circumstances the alcoholiccontent may be up to about 8%.

Non-limiting benefits include:

-   -   the ability of the resultant foam to conserve of skin barrier        properties;    -   the reduction of skin irritation;    -   satisfactory or increased penetration of the active or        beneficial agent whilst replenishing the skin for example by        moisturizing or adding fats or oils;

The ratio between the stabilizing agent or polymeric agent andpetrolatum is determined according to the desirable level of petrolatumand taking into account appropriate and desirable pharmacologic andsafety properties of the product. Typically, the stabilizing agent topetrolatum ranges between about 1:5 and about 1:100, for example, about1:5, about 2:15, about 1:10, about 2:25, about 1:15, about 2:35, about1:20, about 2:45 and about 1:25, about 1:30; about 1:40 about 1:50;about 1:60; about 1:70; about 1:80; about 1:90; about 1:100 preferablybetween about 1:15 to about 1:60.

Low Water Content Formulations

As indicated herein the aforesaid description of the non-aqueousformulations is also generally applicable to the low water contentformulations herein with where necessary appropriate changes as would beappreciated by a man of the art. The non limiting examples given in theSummary also apply here. Thus, the previous section may be read andapplied to these formulations with these points in mind. Otherembodiments by way of example are specifically described below.

The present invention relates to stable non-alcoholic foamablepetrolatum based carriers and pharmaceutical and cosmetic emulsioncompositions comprising a petrolatum or mixtures thereof, a surfactant,and a propellant and in certain cases a solvent, with and without theaddition of an active agent, wherein the foam produced by the carrier orpharmaceutical composition when packaged in an aerosol container andreleased has a foam hardness in the range of about 5 g to about 100 g.Unexpectedly some of the compositions show hardness measurements in theupper range and yet have a relatively soft feeling.

The present invention relates to stable non-alcoholic foamablepetrolatum based carriers and pharmaceutical and cosmetic emulsioncompositions with very high viscosity measurements prior to addition ofthe propellant. In one or more embodiments the pre foam formulation canhave a wide range of viscosity from about 500,000 to about 12,000 CP orless. For example, from about 500,000 to about 300,000, from about400,000 to about 150,000; from about 375,000 to about 225,000; fromabout 225,000 to about 75,000; from about 125,000 to about 12,000 orless.

It was unexpectedly discovered that after dissolving the propellant intopre foam formulations with such high viscosity that there is a change inthe petrolatum such that it is shakable and flowable. It is believedthat in certain embodiments some compositions may be marginally orapparently non shakable and still have a degree of flowability such thata good quality foam can be expelled from the canister.

The present invention also relates to stable non-alcoholic foamablepetrolatum based pharmaceutical and cosmetic compositions comprisingpetrolatum mixtures. It was discovered that by combining appropriateamounts of different types of petrolatum foams which are able to mimicthe barrier properties of petrolatum ointments and particularlypetrolatum based barrier creams for nappy rash. In one embodiment a lowmelting point petrolatum is mixed with a petrolatum with a highermelting point. In certain embodiments the major petrolatum is the lowermolecular weight petrolatum. In other embodiments the petrolatum ismixed in a ratio for example, of about 5:1; 4:1; 3:1; 2:1; or 1:1 oflower melting point to higher melting point petrolatum. In someembodiments the ratio of mixture can be of higher melting point to lowermelting point.

In an embodiment it was surprising found that it was possible to excludestabilizers other than a surfactant and still prepare a creamy stablefoam without and with an active pharmaceutical ingredient.

In one or more embodiments there is provided a foamable vehicle that issuitable for use as a base for delivery of not merely one type of activepharmaceutical ingredient (API) but is adaptable for use with one ormore API's from a wide range of different types of API's with relativelyminimal or minor adjustment to the vehicle. For example, forcompositions with a solvent, by altering the amount of a component or bythe addition of a buffer that provides a pH in an aqueous environment ora postulated pH in a non-aqueous environment in which the API is stableand or by use of a chelating agent as is described below as would beappreciated by a person skilled in the art.

In one or more embodiments there is provided a stable non-alcoholicfoamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant; at a concentration of about 0.1% to    about 15% by weight; prior to the addition of propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is stored in an aerosol    container and upon release expands to form a breakable foam and    wherein the carrier is shakable or substantially so.

In one or more embodiments there is provided a stable non-alcoholicfoamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant; at a concentration of about 0.1% to    about 15% by weight; prior to the addition of propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is flowable or flowable    to a degree when stored in an aerosol container and upon release    expands to form a breakable foam.

In one or more embodiments there is provided a stable non-alcoholicfoamable carrier composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight; prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is stored in an aerosol    container and upon release expands to form a breakable foam having a    foam hardness in the range of about 5 g to about 100 g and wherein    the carrier is shakable or substantially so.

In one or more embodiments there is provided a stable non-alcoholicfoamable pharmaceutical or cosmetic composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) at least one solvent; and-   (5) an effective amount of an active pharmaceutical agent; and    wherein the carrier is resistant to creaming at 3000 rpm for at    least 10 minutes;-   wherein the composition is stored in an aerosol container and upon    release expands to form a breakable foam and wherein the carrier is    shakable or substantially so.

The present invention relates to a stable non-alcoholic foamablepharmaceutical or cosmetic composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) a solvent; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the composition is resistant to creaming at 3000 rpm for    at least 10 minutes; wherein the composition is flowable or flowable    to a degree when stored in an aerosol container and upon release    expands to form a breakable foam.

In one or more embodiments there is provided a stable non-alcoholicfoamable pharmaceutical or cosmetic composition comprising:

-   (1) a petrolatum or mixtures thereof, at a concentration of about    50% to about 95% by weight prior to the addition of propellant;-   (2) at least one surfactant or surfactant system; at a concentration    of about 0.1% to about 15% by weight prior to the addition of    propellant;-   (3) at least one liquefied or compressed gas propellant at a    concentration of about 10% to about 35% by weight of the total    composition;-   (4) a solvent; and-   (5) an effective amount of an active pharmaceutical agent;-   and wherein the carrier is resistant to creaming at 3000 rpm for at    least 10 minutes;-   wherein the composition is stored in an aerosol container and upon    release expands to form a breakable foam having a foam hardness in    the range of about 5 g to about 100 g and wherein the carrier is    shakable or substantially so.

In a further embodiment the foam hardness is in the range of about 10 gto about 90 g or more, preferably about 30 g to about 85 g.

In a further embodiment the surfactant or surfactant system ispreferably between about 1% to about 10% by weight of the compositionprior to the addition of propellant.

In a further embodiment the surfactant and its amount is selected sothat the composition is sufficiently shakable so that substantiallyuniform foam extrusion is possible. To this extent the maximum effectiveamount of surfactant that may be used may be limited by the need forshakability.

In a further embodiment the surfactant and its amount is selected sothat the composition is sufficiently flowable so that substantiallyuniform foam extrusion is possible. To this extent the maximum effectiveamount of surfactant that may be used may be limited by the need forsome flowability.

In a further embodiment the propellant is preferably between about 10%to about 30% by weight of the composition.

In a further embodiment the propellant is preferably between about 14%to about 26% by weight of the composition.

In a further embodiment the active ingredient may be partially insolublein a phase of the emulsion. In other embodiments it may be insoluble ina phase.

In one or more embodiments a stabilizing agent may alone or incombination with petrolatum help to ameliorate, counteract, or overcomeundesirable effects and drawbacks of an API, such as destabilization, onan emulsion vehicle, on a phase, on micelles or on an interphase. In oneor more embodiments the stabilizing agent comprises a polymeric agentsuch as ASOS, an alkyl lactate such as C-12 to C-15 alkyl lactate,carboxymethyl cellulose sodium and microcrystalline cellulose ormethocel and xantham gum. For example, in preparing stable non-alcoholicpetrolatum foamable pharmaceutical water in oil emulsion compositionssuitable for delivery of an active pharmaceutical ingredient acombination of surfactants, a metal starch, and an alkyl lactate can beused to achieve a stable foam.

When water is present the foamable composition can be an emulsion, ormicroemulsion, or nanoemulsion.

In an embodiment these low water content formulations and foams are alsonon-silicone and or non-alcoholic or substantially so.

General

Solvent and optional ingredients are added to complete the total mass ofthe foamable carrier to 100%.

All % values are provided on a weight (w/w) basis. In the examples thecomponents of the composition are added to a total of 100% exclusive ofthe propellant.

Aging

Formulation of foam is a very delicate balance between the functionalinactive ingredients, excipients, which contribute to bubble size,viscosity, hardness look and feel and stability. In order to assureaccurate and continuous foam actuation, the Foam Formulation shouldduring its intended life or use period be liquid and shakable in thecanister, otherwise it will not flow easily and completely towards andthrough the valve. In the context of high levels of petrolatum foamableformulations it is possible as an exception for the composition to bemarginally or apparently non shakable whilst the composition has asufficient degree of flowability under pressure of the propellant thatit is possible to obtain a good quality of foam.

Stability of compositions of petroleum and solvents substantialitymiscible therein together with surfactants and other additives isdesired. Testing for aging as reflected by creaming or phase separationwhilst normally considered in the realm of emulsions may also be used toexplore waterless compositions. The concept of creaming in waterlesssingle phase compositions may be artificial and not accuratelyapplicable and requires investigation. Resistance to creaming or phaseseparation can be determined by taking a sample and subjecting it to asignificant G force through centrifugation to simulate acceleratedaging. Waterless compositions in which petrolatum is the main componentmay have some inherent resistant to “creaming” or phase separationbecause of the physical properties of petrolatum. In the context offoamable compositions improved physical stability may be obtained by anappropriate choice of product viscosity through use of different blendsof petrolatum together with one or more solvents substantially misciblein petrolatum plus a surfactant or surfactant system optionally incombination with stabilizing agents and or viscoelastic agents, whichcan provide suitable rheology whilst retaining the requirements ofshakability or at least flowability. In the context the solvents and thesurfactants used can have a considerable influence on rheology,shakability and flowability.

Where there is an emulsion, for example, when water and surfactants areformulated with petrolatum stability of emulsions and resilience tocreaming is desired. Emulsions in which petrolatum is the main singlecomponent or is the main component may be inherently resistant tocreaming because of the physical properties of petrolatum. In thecontext of foamable emulsion compositions it has been discovered thatimproved physical stability is obtained by an appropriate choice ofproduct viscosity through use of different blends of petrolatum plus asurfactant or surfactant system optionally in combination withstabilizing agents and or viscoelastic agents, which can providesuitable rheology whilst retaining the requirements of shakability or atleast flowability and by controlling droplet size.

By creaming it is meant that an upper layer forms. The creaming value isdefined as the relative volume of the creamed phase and the total volumethe sample. The expression used for calculation of the creaming volumeis as follows:

${\% \mspace{14mu} {Creaming}} = {\frac{V_{{Creamed}\mspace{14mu} {Phase}}}{V_{total}} \times 100}$

Creaming values are between 1% and 99%, accordingly. 100% means “nocreaming” which is the desirable best score. 0% (Zero value) indicatesphase separation and is the worst score.

By physically durable it is intended that the formulation is capable ofphysically withstanding to a substantial degree at least one ofcentrifugation at about 1000 rpm for non-aqueous formulations and atabout 3000 rpm for emulsions for about 10 minutes in each case; or one,or possibly more freeze thaw cycles; or a period of time at an elevatedtemperature of say 30° C. or say 40° C. for say about one month; or aprolonged period of time at room temperature for say about three months.In preferred embodiments the formulations can withstand 3 months at 30°C. or 40° C. and or 6 months at room temperature.

In an embodiment the composition should exhibit pseudoplasticrheological behavior.

By selective use of appropriate stabilizing surfactant, co-surfactantsand optionally stabilizing polymers and foam adjuvants the compositionscan be stabilized. By appropriate selection of agents, surfactants andsolvent in a petrolatum base composition to facilitate biocompatibilityand to achieve the appropriate balance of physical properties, it ispossible to prepare formulations that are resilient to aging whensubjected to centrifugation which could be extrapolated to reflect areasonable stable shelf life.

Petrolatum

Petrolatum is known by various names including yellow soft paraffin,yellow petrolatum, mineral jelly; and petroleum jelly. Petrolatum is apurified mixture of semisolid saturated hydrocarbons having the generalformula C_(n)H_(2n+2), and is obtained from petroleum. The hydrocarbonsconsist mainly of branched and unbranched chains although some cyclicalkanes and aromatic molecules with paraffin side chains may also bepresent. Some forms may contain a suitable stabilizer (antioxidant). Itis mainly used as an emollient and ointment base in topicalpharmaceutical formulations creams and transdermal applications.Therapeutically, sterile gauze dressings containing petrolatum may beused for nonadherent wound dressings. Petrolatum is additionally widelyused in cosmetics and in some food applications. It is odorless, andtasteless.

The rheological properties of petrolatum are determined by the ratio ofthe unbranched chains to the branched chains and cyclic components ofthe mixture. Petrolatum contains relatively high amounts of branched andcyclic hydrocarbons, in contrast to paraffin, which accounts for itssofter character and makes it an ideal ointment base. In one or moreembodiments, a petrolatum or a petrolatum mixture is selected such thatit has a quality of relative softness.

Petrolatum is an inherently stable material. On exposure to light anyimpurities present may be Oxidation may be inhibited by the inclusion ofa suitable antioxidant such as butylated hydroxyanisole, butylatedhydroxytoluene, or alpha tocopherol.

In preparing Petrolatum compositions they should not be heated forextended periods above the temperature necessary to achieve completefluidity (approximately 75° C.).

Various grades of petrolatum are commercially available, which vary intheir physical properties depending upon their source and refiningprocess. Petrolatum obtained from different sources may therefore behavedifferently in a formulation. White petrolatum is a preferred petrolatumfor use in cosmetics and pharmaceuticals, Additives, such asmicrocrystalline wax, may be used to add body to petrolatum.

The petrolatum used in the present invention was examinedmicroscopically and no wax crystallization was observed. Thus, in one ormore embodiments the petrolatum selected shows no tendency to waxcrystallization. In one or more further embodiments the petrolatum basedfoamable carriers and compositions are free or substantially free of waxcrystallization. In one or more further embodiments the petrolatum basedfoamable carriers and compositions are free or substantially free of waxcrystallization when the petrolatum level is about 50% to about 95% byweight in the composition before the addition of propellant.

MMP Inc state in their sales booklet on Sofinetic™ LMP (Rev 02/05 KVB)that they conducted studies with varying grades of petroleum USP toavoid formation of wax crystals in emulsions containing 20% petrolatumand that MMP's supersoft grade incorporated into low emulsifier contentformulations containing 20% petroleum has been shown to eliminateundesirable crystallization of wax. They further state that whencompared to similar compositions made with a higher melting point gradeof petrolatum the Sofinetic™ LMP exhibited no tendency to waxcrystallization.

In certain embodiments, in the context, the term petrolatum relates toany fatty substance, having Theological properties and metingtemperature patterns in the same range as described above forpetrolatum.

Unctuous Additives

A “unctuous additive” as used herein refers to a greasy, fatty, waxy oroily material, including liquids, semi solids and solids which can bemixed with petrolatum to alter refine or improve the petrolatum basedcompositions. In one or more embodiments a small, moderate medium orlager amount of one or more unctuous additive may be blended withpetrolatum provided the petrolatum remains the single largest componentof the composition. In one or more other embodiments the unctuousadditive can be the major component of the blend with petrolatum. Evenif not the main component the properties of petrolatum at the levels ofabout at least 25% in the present invention it may still have a major ordominating influence on the composition. In any event unctuous additivesmay also have a role in effecting the solubility of an API. Unexpectedlyit has been noted that in certain cases where an oil is combined withpetrolatum the resultant foam has a significantly lower density.

Non limiting examples of unctuous additives that may be used in thepharmaceutical composition may be natural or synthetic or a syntheticderivative and, include higher aliphatic hydrocarbons, animal orvegetable fats, greases and oils, waxes, and combinations thereof.

In one or more embodiments, specific non limiting examples are higheraliphatic hydrocarbons, mineral jelly and fractions thereof, paraffin,squalane, ceresin, mineral oil and the like.

In one or more embodiments, specific non limiting examples of the waxesinclude beeswax, carnauba wax, microcrystalline wax, candililla wax,berry wax, montan wax, polyethylene wax and ethylene vinyl acetate (EVA)copolymers spermaceti, lanolin, wool wax, wool fat, wax blend, solidparaffin, oxidized wax, waxy solids or waxy semi-solids, synthetic wax'sand the like.

In one or more embodiments, non limiting specific examples of the animalor vegetable fats and oils include, triglycerides, olive oil, almondoil, avocado oil, borage oil, castor oil, cocoa butter, palm oil, turtleoil, cod-liver oil, whale oil, beef tallow, butter fat, shea butter,shorea butter, and the like.

In one or more embodiments, the above-described unctuous additive may beused alone or in combination with petrolatum.

The use of high melting point hydrocarbons, such as petrolatum can beocclusive when applied to the skin. In one or more embodiments, when anextensive refatting or moisturizing effect is required, then petrolatumin concentrations of more than 25% preferably more than 50% to about 95%prior to the addition of propellant is included in the compositions.

In order to derive, develop or optimize a composition, which is readilyfoamable upon release from a pressurized container, additionalcomponents may also be introduced, as provided herein below.

Hydrophobic Solvents

Further in one or more embodiments petrolatum and petrolatum mixturesmay also be combined with one or more hydrophobic solvents or carriers,which are materials suitable for use to blend with or act as a carrierfor the petrolatum emollients. They may also have a further role ineffecting the solubility of an API.

In one or more other embodiments the hydrophobic solvents or carriersare ester oils. Specific non limiting examples of the ester oils includeisopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate,octyldodecyl myristate, di-isopropyl adipate, isocetyl myristate,di-isopropyl sebacate, and the like.

In one or more other embodiments the hydrophobic solvents or carriersare higher alcohols. Specific non limiting examples of the higheralcohols include cetyl alcohol, oleyl alcohol, isostearyl alcohol,octyldodecanol and the like.

According to one or more embodiments, hydrophobic solvents or carriersare liquid oils originating from vegetable, marine or animal sources.Suitable liquid oil includes saturated, unsaturated or polyunsaturatedoils. By way of example, the unsaturated oil may be olive oil, corn oil,soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil,sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil,herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil,evening primrose oils or mixtures thereof, in any proportion.

Suitable hydrophobic solvents or carriers also include polyunsaturatedoils containing poly-unsaturated fatty acids. In one or moreembodiments, the unsaturated fatty acids are selected from the group ofomega-3 and omega-6 fatty acids. Examples of such polyunsaturated fattyacids are linoleic and linolenic acid, gamma-linoleic acid (GLA),eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Suchunsaturated fatty acids are known for their skin-conditioning effect,which can contribute to the therapeutic benefit of the present foamablecomposition. Thus, the hydrophobic solvent can include at least 3%preferably at least 6% of an oil selected from omega-3 oil, omega-6 oil,and mixtures thereof.

In the context, oils that possess therapeutically beneficial propertiesare termed as “therapeutically active oil.”

Another class of hydrophobic solvents or carriers is the essential oils,which are also considered therapeutically active oils, and which containactive biologically occurring molecules and, upon topical application,exert a therapeutic effect. Non-limiting examples of essential oilsinclude rosehip oil, which contain retinoids and is known to reduce acneand post-acne scars, and tea tree oil, which possess antibacterial,antifungal and antiviral properties. Other examples of essential oilsare oils of anise, basil, bergemont, camphor, cardamom, carrot, canola,cassia, catnip, cedarwood, citronella, clove, cypress, eucalyptus,frankincense, garlic, ginger, grapefruit, hyssop, jasmine, jojova,lavender, lavandin, lemon, lime, mandarin, marjoram, myrrh, neroli,nutmeg, orange, peppermint, petitgrain, rosemary, sage, spearmint, staranise, tangerine, thyme vanilla, verbena and white clover.

Another class of therapeutically active oils is liquid hydrophobicplant-derived oils, which are known to possess therapeutic benefits whenapplied topically.

Silicone oils also may be used and are desirable due to their known skinprotective and occlusive and antifriction properties. Moreover they maymask to some extent the tacky greasy feeling of petrolatum on the skin.Suitable silicone oils include non-volatile silicones, such as polyalkylsiloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and polyethersiloxane copolymers, polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. Silicone oils arealso considered therapeutically active oil, due to their barrierretaining and protective properties. However, silicone oils are notessential. They are foam defoamers and therefore if included are ideallyused in relatively small amounts, such as less than about 5% if there ismore than 50% petrolatum, and in other cases where the petrolatum isunder about 50% then the silicones should be less than about 1%. Tocounteract to some extent the defoaming properties extra surfactant andor foam adjuvant may be usefully added. If volatile silicones are usedthey evaporate from the skin and effect the deposited composition andcan interfere with its occlusive properties and may cause dryness. In apreferred embodiment there is no silicone or less than 1%. When thelevel of petrolatum is at least about 50% or more then higher levels ofsilicone may be used.

A further class of hydrophobic solvents or carriers includes hydrophobicliquids, selected from the family of organic liquids described as“emollients.” Emollients possess a softening or soothing effect,especially when applied to body areas, such as the skin and mucosalsurfaces. Examples of suitable emollients include isopropyl myristate,isopropyl palmitate, isopropyl isostearate, diisopropyl adipate,diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyllactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate,tocopheryl linoleate, wheat germ glycerides, arachidyl propionate,myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyllanolate, pentaerythrityl tetrastearate, neopentylglycoldicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate,myristyl myristate, octyl dodecanol, sucrose esters of fatty acids andoctyl hydroxystearate.

In one or more embodiments the petrolatum based foamable carrier andcomposition comprises a hydrophobic solvent selected from the groupconsisting of:

-   -   1 a high-melting point hydrocarbon;    -   2 a liquid oil originating from vegetable, marine or animal        sources;    -   3 an oil selected from the group consisting of (1) a saturated        oil; (2) an unsaturated oil; and (3) a polyunsaturated oil;    -   4 an oil selected from the group consisting of olive oil, corn        oil, soybean oil, canola oil, cottonseed oil, coconut oil,        sesame oil, sunflower oil, borage seed oil, syzigium aromaticum        oil, hempseed oil, herring oil, cod-liver oil, salmon oil,        flaxseed oil, wheat germ oil and evening primrose oil;    -   5 an poly-unsaturated fatty acid selected from the group        consisting of (1) an omega-3 fatty acid and (2) an omega-6 fatty        acid;    -   6 an poly-unsaturated fatty acid selected from the group        consisting of linoleic acid, linolenic acid, gamma-linoleic acid        (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid        (DHA);    -   7 a therapeutically active oil;    -   8 an essential oil;    -   9 an oil derived from a plant selected from the group consisting        of anise, basil, bergemont, camphor, cardamom, carrot, canola,        cassia, catnip, cedarwood, citronella, clove, cypress,        eucalyptus, frankincense, garlic, ginger, grapefruit, hyssop,        jasmine, jojova, lavender, lavandin, lemon, lime, mandarin,        marjoram, myrrh, neroli, nutmeg, orange, peppermint, petitgrain,        rosemary, rosehip, sage, spearmint, star anise, tea tree,        tangerine, thyme vanilla, verbena and white clover;    -   10 a silicone oil;    -   11 an oil selected from the group consisting of a polyalkyl        siloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a        polyether siloxane copolymer, a polydimethylsiloxane and a        poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer;    -   12 a hydrophobic emollient; and    -   13 an oil selected from the group consisting of isopropyl        myristate, isopropyl palmitate, isopropyl isostearate,        diisopropyl adipate, diisopropyl dimerate, maleated soybean oil,        octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl        acetate, cetyl acetate, tocopheryl linoleate, wheat germ        glycerides, arachidyl propionate, myristyl lactate, decyl        oleate, propylene glycol ricinoleate, isopropyl lanolate,        pentaerythrityl tetrastearate, neopentylglycol        dicaprylate/dicaprate, isononyl isononanoate, isotridecyl        isononanoate, myristyl myristate, octyl dodecanol, sucrose        esters of fatty acids and octyl hydroxystearate.

In one or more embodiments the petrolatum based foamable carrier andcomposition comprises a hydrophobic solvent in a moderate or largeramount.

Polypropylene Glycol (PPG) Alkyl Ethers

In the context, a polypropylene glycol alkyl ether (PPG alkyl ether) isa liquid, water-insoluble propoxylated fatty alcohol, having themolecular formula of RO(CH₂CHOCH₃)_(n); wherein “R” is astraight-chained or branched C₄ to C₂₂ alkyl group; and “n” is in therange between 4 and about 50.

(PPG alkyl ethers), are organic liquids that function asskin-conditioning agent in pharmaceutical and cosmetic formulations.They possess exceptional emollient effect, side by side with enhancedsolvency properties, which facilitates solubilization of active agentsin a composition comprising a PPG alkyl ether. PPG alkyl ethers offerthe following advantages when used as a component in the foamablecomposition:

-   -   Due to the polypropylene glycol moiety, PPG alkyl ethers possess        certain surface active properties and they assist in the        coupling of polar and non-polar oils in an emulsion formulation.    -   PPG alkyl ethers are non-occlusive; offering a long-lasting and        velvety feel.    -   They are chemically stable at extreme pH conditions;    -   Excellent solvency properties, particularly with difficult to        formulate active agents    -   When combined with certain surfactants, such as Brij 72 and Brij        721, PPG alkyl ethers form oleosomes and/or liquid crystal        structures, which provide long lasting moisturization, excellent        spreading as well as prolonged hydration properties

Exemplary PPG alkyl ethers include PPG-2 butyl ether, PPG-4 butyl ether,PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butylether, PPG-15 butyl ether, PPG-16 butyl ether, PPG-17 butyl ether,PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butylether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether,PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetylether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether,PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristylether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether,PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-50 oleyl ether, PPG-11stearyl ether. Preferred PPG alkyl ethers according to the presentinvention include PPG-15 stearyl ether (also known as Earlamol E®,Unichema), PPG-2 butyl ether, PPG-9-13 butyl ether and PPG-40 butylether. PPG alkyl ethers can be incorporated in the foamable compositionin a concentration preferably between about 1% and about 20%, morepreferably between about 3% and about 15%.

The sensory properties of foams containing PPG alkyl ethers arefavorable, as revealed by consumer panel tests.

Surprisingly, it has been discovered that PPG alkyl ethers also reducethe degree of inflammability of a foam, as demonstrated in a standardinflammability test according to European Standard prEN 14851, titled“Aerosol containers. According to this standard, a product is consideredinflammable if a stable flame appears following ignition, which is atleast 4 cm high and which is maintained for at least 2 seconds. In anembodiment, the concentration of the PPG alkyl ether is sufficient toreduce the degree of inflammability, of a composition when compared withthe same composition without the PPG alkyl ether.

Surface Active Agent

The composition further contains a surface-active agent. Surface-activeagents (also termed “surfactants”) include any agent linking oil andwater in the composition, in the form of emulsion. A surfactant'shydrophilic/lipophilic balance (HLB) describes the emulsifier's affinitytoward water or oil. HLB is defined for non-ionic surfactants. The HLBscale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic),with 10 representing an equal balance of both characteristics.Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilicsurfactants form oil-in-water (o/w) emulsions. The HLB of a blend of twoemulsifiers equals the weight fraction of emulsifier A times its HLBvalue plus the weight fraction of emulsifier B times its HLB value(weighted average). In many cases a single surfactant may suffice. Inother cases a combination of two or more surfactants is desired.Reference to a surfactant in the specification can also apply to acombination of surfactants or a surfactant system. As will beappreciated by a person skilled in the art which surfactant orsurfactant system is more appropriate is related to the vehicle andintended purpose. In general terms a combination of surfactants isusually preferable where the vehicle is an emulsion. In an emulsionenvironment a combination of surfactants can be significant in producingbreakable forms of good quality. In a waterless or substantiallywaterless environment it has been discovered that the presence of asurfactant or combination of surfactants can also be significant inproducing breakable forms of good quality. It has been furtherdiscovered that the generally thought considerations for HLB values forselecting a surfactant or surfactant combination are not always bindingfor emulsions and that good quality foams can be produced with asurfactant or surfactant combination both where the HLB values are in ortowards the lipophilic side of the scale and where the HLB values are inor towards the hydrophilic side of the scale.

It has been further discovered that the physical nature of thesurfactant or combination thereof can affect the quality of foamproduced. For example and in very general oversimplified terms thepresence of a solid or waxy surfactant may help where the composition ismore liquid or less viscous in nature and similarly where a formulationis less liquid and more viscous the presence of a liquid surfactant mayhelp. More particularly a combination of a solid or waxy surfactant witha liquid surfactant may be of significance and the ratio between themmay be adjusted to take into account to an extent whether thecomposition is otherwise more liquid or otherwise more viscous innature. The position is more complex than this since the presence andinteraction of other agents such as foam adjuvants, polymeric agents aswell as unctuous additives and hydrophobic agents all have an influenceon achieving a breakable foam of quality

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9. Lower HLB values may in certainembodiments be more applicable.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 14. Mid range HLB values may incertain embodiments be more suitable.

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 andabout 19, or more than one surface active agent and the weighted averageof their HLB values is between about 9 and about 19. In a waterless orsubstantially waterless environment a wide range of HLB values may besuitable.

According to one or more embodiments a wide range of HLB values givingabout an average mid range can be achieved with combinations of two,three or more surfactants. For example, the following provides anaverage of 9.36:

Behenyl alcohol 1.9 ceteth 20 15.7 steareth 2 4.7 GMS 3.4 Span 80 4.3Tween 20 16.7

Preferably, the composition contains a non-ionic surfactant. Nonlimitingexamples of possible non-ionic surfactants include a polysorbate,polyoxyethylene (20) sorbitan monostearate, sorbitan monostearate,polyoxyethylene (20) sorbitan monooleate, sorbitan laurate; apolyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59;a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether,polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21,brij 721, brij 38, brij 52, brij 56 and brij W1, behenyl alcohol; asucrose ester, a partial ester of sorbitol and its anhydrides, sorbitanmonolaurate, sorbitan monolaurate, a monoglyceride, a diglyceride,isoceteth-20 and mono-, di- and tri-esters of sucrose with fatty acids.In certain embodiments, suitable sucrose esters include those havinghigh monoester content, which have higher HLB values.

In certain embodiments, surfactants are selected which can provide aclose packed surfactant layer. To achieve such objectives combinationsof at least two surfactants are selected. Preferably, they should becomplex emulgators and more preferably they should both be of a similarmolecular type; for example, a pair of ethers, like steareth 2 andsteareth 21, or a pair of esters, for example, PEG-40 stearate andpolysorbate 80. Ideally, the surfactants can be ethers. In certaincircumstances POE esters cannot be used and a combination of sorbitanlaurate and sorbitan stearate or a combination of sucrose stearic acidester mixtures and sodium laurate may be used. All these combinationsdue to their versatility and strength may also be used satisfactorilyand effectively with ether formulations, although the amounts andproportion may be varied according to the formulation and its objectivesas will be appreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin mayalso a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB˜4.9); glyceryl monostearate/PEG 100stearate (Av HLB˜11.2); stearate Laureth 4 (HLB˜9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monocetyl ether). More exemplarystabilizing surfactants which may be suitable for use in the presentinvention are found below.

PEG-Fatty Acid Monoester Surfactants Chemical name Product example nameHLB PEG-30 stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-45 stearate Nikkol MYS-45(Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-100 stearate Myrj 59, Arlacel165 (ICI) 19

PEG-Fatty Acid Diester Surfactants: Chemical name Product example nameHLB PEG-4 dilaurate Mapeg .RTM. 200 DL (PPG), 7 Kessco .RTM.PEG 200 DL(Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 distearate Kessco .RTM. 200 5DS (Stepan.sub) PEG-32 dioleate Kessco .RTM. PEG 1540 DO 15 (Stepan)PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 disterateCithrol 4DS series (Croda) >10 PEG-20 glyceryl oleate Tagat .RTM. O(Goldschmidt) >10

Transesterification Products of Oils and Alcohols Chemical name Productexample name HLB PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11PEG-40 hydrogenated Cremophor RH 40 (BASF), 13 castor oil Croduret(Croda), Emulgin HRE 40 (Henkel)

Polyglycerized Fatty Acids, such as: Chemical name Product example nameLB Polyglyceryl-6 dioleate Caprol .RTM. 6G20 (ABITEC); 8.5 PGO-62(Calgene), PLUROL OLEIQUE CC 497 (Gattefosse)Hodag

PEG-Sorbitan Fatty Acid Esters Chemical name Product example name HLBPEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 monopalmitate (Croda)PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 monostearate (Croda)PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 (Croda) PEG-20sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 (Croda)

Polyethylene Glycol Alkyl Ethers Chemical name Product example name HLBPEG-2 oleyl ether oleth-2 Brij 92/93 (Atlas/ICI) 4.9 PEG-3 oleyl etheroleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether oleth-5 Volpo 5 (Croda)<10 PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 96/97(Atlas/ICI) PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 98/99(Atlas/ICI) PEG-4 lauryl ether Laureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23lauryl ether Laureth-23Brij 35 (Atlas/ICI) 17 PEG-10 stearyl ether Brij76 (ICI) 12 PEG-2 cetyl ether Brij 52 (ICI) 5.3

Sugar Ester Surfactants Chemical name Product example name HLB Sucrosedistearate Sisterna SP50, Surfope 1811 11

Sorbitan Fatty Acid Ester Surfactants Chemical name Product example nameHLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 (Croda),Arlacel 20 (ICI) Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7(Croda), Nikkol SP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI),Crill 4 4.3 (Croda), Crill 50 (Croda) Sorbitan monostearate Span-60(Atlas/ICI), Crill 3 4.7 (Croda), Nikkol SS-10 (Nikko)

In one or more embodiments the surface active agent is a complexemulgator in which the combination of two or more surface active agentscan be more effective than a single surfactant and provides a morestable emulsion or improved foam quality than a single surfactant. Forexample and by way of non-limiting explanation it has been found that bychoosing say two surfactants, one hydrophobic and the other hydrophilicthe combination can produce a more stable emulsion than a singlesurfactant. Preferably, the complex emulgator comprises a combination ofsurfactants wherein there is a difference of about 4 or more unitsbetween the HLB values of the two surfactants or there is a significantdifference in the chemical nature or structure of the two or moresurfactants.

Specific non limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as Brij 59/Brij 10; Brij 52/Brij10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721);combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59;combinations of sucrose esters, such as Surphope 1816/Surphope 1807;combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span60; combinations of sucrose esters and sorbitan esters, such as Surphope1811 and Span 60; combinations of liquid polysorbate detergents and PEGcompounds, such as Tween 80/PEG-40 stearate; methyl glucasosequistearate; polymeric emulsifiers, such as Permulen (TR1 or TR2);liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1),Nikomulese (41) and Montanov (68) and the like.

In certain embodiments the surfactant is preferably a combination ofsteareth-2 and steareth-21; in certain other embodiments the surfactantis a combination of polysorbate 80 and PEG-40 stearate. In certain otherembodiments the surfactant is a combination of glyceryl monostearate/PEG100 stearate.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of two incompatible components on a nanometerscale. Soap is an everyday example of a lyotropic liquid crystal.Certain types of surfactants tend to form lyotropic liquid crystals inemulsions interface (oil-in-water) and exert a stabilizing effect. Nonlimiting examples of surfactants with postulated tendency to forminterfacial liquid crystals are: phospholipids, alkyl glucosides,sucrose esters, sorbitan esters. In certain embodiments surfactantswhich tend to form liquid crystals may improve the quality of foamsproduced.

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.

In one or more embodiments the at least one surface active agent isliquid.

In one or more embodiments the at least one surface active agent issolid, semi solid or waxy.

It should be noted that HLB values may not be so applicable to non ionicsurfactants, for example, with liquid crystals or with silicones.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.

In one or more embodiments, the surface-active agent includes at leastone non-ionic surfactant. Ionic surfactants are known to be irritants.Therefore, non-ionic surfactants are preferred in applications includingsensitive tissue such as found in most mucosal tissues, especially whenthey are infected or inflamed. Non-ionic surfactants alone can provideformulations and foams of good or excellent quality in the carriers andcompositions described herein.

Thus, in a preferred embodiment, the surface active agent, thecomposition contains a non-ionic surfactant. In another preferredembodiment the composition includes a mixture of non-ionic surfactantsas the sole surface active agent. Yet, in additional embodiments, thefoamable composition includes a mixture of at least one non-ionicsurfactant and at least one ionic surfactant in a ratio in the range ofabout 100:1 to 6:1. In one or more embodiments, the non-ionic to ionicsurfactant ratio is greater than about 6:1, or greater than about 8:1;or greater than about 14:1, or greater than about 16:1, or greater thanabout 20:1. In further embodiments, surface active agent comprises acombination of a non-ionic surfactant and an ionic surfactant, at aratio of between 1:1 and 20:1.

In one or more embodiments, a combination of a non-ionic surfactant andan ionic surfactant (such as sodium lauryl sulphate andcocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1,or at a ratio of 4:1 to 10:1; for example, about 1:1, about 4:1, about8:1, about 12:1, about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1,for example, about 4:1, about 6:1, about 8:1 and about 10:1.

In selecting a suitable surfactant or combination thereof it should beborne in mind that the upper amount of surfactant that may be used maybe limited by the shakability of the composition. In general terms, asthe amount of non liquid surfactant is increased the shakability of theformulation reduces until a limitation point is reached where theformulation becomes non shakable and unsuitable. Thus in an embodimentany effective amount of surfactant may be used provided the formulationremains shakable. In other certain exceptional embodiments the upperlimit may be determined by flowability such as in circumstances wherethe composition is marginally or apparently non shakable. Thus in anembodiment any effective amount of surfactant may be used provided theformulation remains flowable.

In certain embodiments the amount of surfactant or combination ofsurfactants is between about 0.05% to about 20%; between about 0.05% toabout 15%. or between about 0.05% to about 10%. In a preferredembodiment the concentration of surface active agent is between about0.2% and about 8%. In a more preferred embodiment the concentration ofsurface active agent is between about 1% and about 6%.

If the composition as formulated is a substantially non shakablecomposition it is nevertheless possible as an exception in the scope forthe formulation to be flowable to a sufficient degree to be able to flowthrough an actuator valve and be released and still expand to form agood quality foam. This surprising and unusual exception may be due oneor more of a number of factors such as the high viscosity, the softness,the lack of crystals, the pseudoplastic or semi pseudo plastic nature ofthe composition and the dissolution of the propellant into thepetrolatum.

In one or more embodiments, the surface-active agent includes mono-, di-and tri-esters of sucrose with fatty acids (sucrose esters), preparedfrom sucrose and esters of fatty acids or by extraction fromsucro-glycerides. Suitable sucrose esters include those having highmonoester content, which have higher HLB values.

Single Phase Compositions and Solvents; Emulsions ((a) w/o; o/w (b)Non-Aqueous)

In one or more embodiments the carrier or composition is non-aqueous oressentially so and comprises a single phase.

In one or more embodiments the carrier or composition comprises asolvent substantially miscible in petrolatum.

In one or more non-aqueous embodiments the carrier or compositioncomprises a hydrophobic solvent in petrolatum wherein preferably thesolvent is an unctuous additive or an oil.

In one or more embodiments the solvent is a PPG alkyl ether, preferablyPPG15 stearyl ether.

In one or more embodiments the solvent is a combination of an unctuousadditive and or an oil and or a PPG alkyl ether. In a preferredembodiment the combination is of an oil and a PPG alkyl ether.Preferably the oil comprises a light mineral oil and the ether comprisesPPG15 stearyl ether.

In one or more embodiments of the present invention the carrier orcomposition comprises a single phase.

In one or more embodiments of the present invention the carrier orcomposition comprises an emulsion.

In one or more embodiments of the present invention the carrier orcomposition comprises a solvent in petrolatum emulsion.

In one or more embodiments of the present invention the carrier orcomposition comprises a solvent in petrolatum emulsion wherein thesolvent is selected from water or a non-aqueous solvent

In one or more embodiments of the present invention the carrier orcomposition comprises water in petrolatum emulsion.

In one or more embodiments of the present invention the carrier orcomposition comprises a unique solvent in petrolatum emulsion whereinthe solvent is a non-aqueous solvent.

In one or more embodiments of the present invention the carrier orcomposition comprises a unique hydrophillic solvent in petrolatumemulsion.

In one or more embodiments of the present invention non limitingexamples of the non-aqueous solvent are solvents such as polyethyleneglycol (PEG), isosorbide derivatives, such as dimethyl isosorbide,propylene gycol (PG), hexylene glycol and glycerin, diethylene glycolmonoethyl ether, a liquid polyethylene glycol, glycofurol,tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO, apyrrolidone, N-methyl pyrrolidones, N-Methyl-2-pyrrolidone,1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-typesurfactant, an alpha hydroxy acid, lactic acid and glycolic acid,hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol(transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol,mannitol, oligosaccharides, monooleate of ethoxylated glycerides havingabout 8 to 10 ethylene oxide units, and cyclodextrins, esters, such asethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl butyrate, propylene glycolmonoacetate, propylene glycol diacetate, .epsilon.-caprolactone andisomers thereof, .delta.-valerolactone and isomers thereof,.beta.-butyrolactone and isomers thereof; and other solubilizers knownin the art, such as dimethyl acetamide.

In an embodiment of the present invention the non-aqueous solvent ismonooctanoin.

In one or more embodiments of the present invention the carrier orcomposition comprises a unique hydrophillic solvent in petrolatumemulsion, wherein the hydrophilic solvent is selected from a liquidpolyethylene glycol, a propylene glycol or dimethyl isosorbide.

Stabilizing Agent

A stabilizing agent is an agent that may have to some extent one or moreof the properties of foam adjuvant, friction ameliorator, gelling agent,look and feel ameliorator, lubricant, stabilizer, anti-destabilizer,surfactant, thickener and viscosity modifier or enhancer.

In one embodiment the stabilizing agent may help to ameliorate,counteract, or overcome undesirable effects and drawbacks of using anpetrolatum emollient.

In one or more embodiments, the stabilizing agent can be, a polymer or apolymeric agent; more specifically it can be an alkyl lactate forexample a C12-15 alkyl lactate, a metal starch for example ASOS orsimilar polymeric derivatives; a hydrophobic starch; a microcrystallinecellulose; a cellulose ether and or long chain polysaccharide; a(alpha-tocopheryl polyethylene glycol succinate); polyoxyethylene alkylethers and crosslinked polyacrylic acid polymers and the like.

Modulating Agent

The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the modulating agent is used in a water inoil (petrolatum) emulsion. In one or more other embodiments themodulating agent is used in a unique waterless emulsion.

In certain embodiments the substance or residue may for example beacidic or basic and potentially alter pH in an emulsion environment orit may be one or more metal ions which may act as a potential catalystin an emulsion environment.

In certain other embodiments the substance or residue may for example beacidic or basic and potentially alter an artificial pH in a waterless orlow water content environment or it may be one or more metal ions whichmay act as a potential catalyst in a waterless or low water contentenvironment.

In one or more embodiments the modulating agent is used to describe anagent which can affect pH in an aqueous solution. The agent can be anyof the known buffering systems used in pharmaceutical or cosmeticformulations as would be appreciated by a man of the art. It can also bean organic acid, a carboxylic acid, a fatty acid an amino acid, anaromatic acid, an alpha or beta hydroxyl acid an organic base or anitrogen containing compound. In certain cases the API, can also affectpH.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the solvent toenable it to “mop up” or “lock” metal ions.

In an embodiment modulating agent is used to describe an agent which caneffect pH in an aqueous solution the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof (i) a waterless or low water content or (ii) an emulsion carrier,composition, foamable carrier or foamable composition or resultant foamdescribed herein.

The substance or residue can be introduced into the formulation from anyone or more of the ingredients, some of which themselves may have acidicor basic properties. For example the polymer or solvent may containbasic residues in which case it may be desirable or beneficial to add anacid. Alternatively the surfactant may contain some acid residues inwhich case the addition of a base may be desirable and beneficial. Insome cases more than one ingredient may contain residues which mayameliorate or compound their significance. For example, if oneingredient provided weak acid residues and another ingredient providedstronger acid residues, the pH in an emulsion environment should belower. In contrast, if one residue was acidic and the other basic thenet effect in the formulation maybe significantly reduced. In somecircumstances the active ingredient may favor an acidic pH or moresignificantly may need to be maintained at a certain acidic pH otherwiseit may readily isomerize, chemically react or breakdown, in which caseintroducing acidic components such as an acidic polymer might be ofhelp. In an embodiment of the present invention sufficient modulatingagent is added to achieve a pH in which the active agent is preferablystable. In another embodiment of the present invention sufficientmodulating agent is added to achieve an artificial pH in which theactive agent is preferably stable.

The terms pH, pKa, and pKb, buffers and the like are used in classicalmeasurements of an aqueous solution. Such measurements are artificial ina waterless environment. Nevertheless, reference to and descriptionbelow of such terms are made for convenience and clarity, since suchterms are well defined and understood with reference to aqueoussolutions and further due to the lack of an appropriate uniform way ofdescribing and identifying the artificial or virtual pH, pK etc in awaterless environment in relation to the present invention. Althoughpredictions of artificial pH can be made using dilution techniques ofmeasurements of waterless formulations diluted in water they areformulation sensitive and specific and have to be carefully calibratedwith complex formulas.

Waterless medium can be polar and protic yet it does not conform toclassical ionic behavior.

In one or more embodiments of the present invention the modulating agentcomprises an organic compound.

In one or more preferred embodiments of the present invention thechelating agent is selected from the group consisting ofethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaaceticacid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA),nitrilotriacetic acid (NTA),O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid (EGTA),trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CyDTA) or apharmaceutically acceptable salt thereof (normally as a sodium salt),more preferably EDTA, HEDTA and their salts; most preferably EDTA andits salts.

In one or more embodiments of the present invention a preferred nonlimiting example of the chelating agent is EDTA. Typically, thechelating and sequestering agent is present in the composition at alevel of up to about 5.0%, preferably 1.0 percent, by weight, of thecomposition.

In one or more embodiments of the present invention the modulating agentmay also be a preservative or an antioxidant or an ionization agent. Anypreservative, antioxidant or ionization agents suitable forpharmaceutical or cosmetic application may be used. Non limitingexamples of antioxidants are tocopherol succinate, propyl galate,butylated hydroxy toluene and butyl hydroxy anisol as well as a wholerange of flavanoids such as quercitin and rutin. Ionization agents maybe positive or may be negative depending on the environment and theactive agent or composition that is to be protected. Ionization agentsmay for example act to protect or reduce sensitivity of active agents.Non limiting examples of positive ionization agents are benzyl coniumchloride, and cetyl pyridium chloride. Non limiting examples of negativeionization agents are sodium lauryl sulphate, sodium lauryl lactylateand phospholipids.

Humectant

A humectant is a substance that helps retain moisture and also preventsrapid evaporation. Non limiting examples are propylene glycol, propyleneglycol derivatives, glycerin, hydrogenated starch hydrosylate,hydrogenated lanolin, lanolin wax, D manitol, sorbitol, sodium2-pyrrolidone-5-carboxylate, sodium lactate, sodium PCA, solublecollagen, dibutyl phthalate, and gelatin. Other examples may be found inthe Handbook of Pharmaceutical Additives published by Gower. In thepresent invention the humectant is preferably a hydrophobic humectant.

Moisturizers

A moisturizer, is a substance that helps retain moisture or add backmoisture to the skin. Examples are allantoin, petrolatum, urea, lacticacid, sodium PCV, glycerin, shea butter, caprylic/capric/stearictriglyceride, candelilla wax, propylene glycol, lanolin, hydrogenatedoils, squalene, sodium hyaluronate and lysine PCA. Other examples may befound in the Handbook of Pharmaceutical Additives published by Gower. Inthe present invention the moisturizer is preferably a hydrophobicmoisturizer. Pharmaceutical compositions may in one or more embodimentsusefully comprise in addition a humectant or a moisturizer orcombinations thereof.

Polar Solvent

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Certain polar solvents, for example propylene glycol andglycerin, possess the beneficial property of a humectant.

In one or more embodiments, the polar solvent is a humectant.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure. In one or more embodiments, the polar solventcontains an diol (a compound that contains two hydroxy groups in itsmolecular structure), such as propylene glycol (e.g., 1,2-propyleneglycol and 1,3-propylene glycol), butaneediol (e.g., 1,4-butaneediol),butaneediol (e.g., 1,3-butaneediol and 1,4-butenediol), butynediol,pentanediol (e.g., 1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol),octanediol (e.g., 1,8-octanediol), neopentyl glycol,2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Other non-limiting examples of polar solvents include pyrrolidones,(such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethylisosorbide, 1,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethylproxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such aslactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Polar solvents are known to enhance the penetration of active agent intothe skin and through the skin, and therefore, their inclusion in thecomposition can be desirable, despite their undesirable skin drying andirritation potential. There is at one level a commonality between thedifferent polar solvents and their penetration enhancement properties.Lower molecular weight alcohols can sometimes be more potent as asolvent, for example by extracting lipids from the skin layers moreeffectively, which characteristic can adversely affect the skinstructure and cause dryness and irritation. Therefore the selection oflower molecular weight alcohols is ideally avoided.

Potent Solvent

In one or more embodiments, the foamable composition includes a potentsolvent, in addition to or in place of one of the hydrophobic solvents,polar solvents or emollients of the composition. A potent solvent is asolvent other than mineral oil that solubilizes a specific active agentsubstantially better than a hydrocarbon solvent such as mineral oil orpetrolatum. For example, a potent solvent solubilizes the active agent 5fold better than a hydrocarbon solvent; or even solubilizes the activeagent 10-fold better than a hydrocarbon solvent.

In one or more embodiments, the composition includes at least one activeagent in a therapeutically effective concentration; and at least onepotent solvent in a sufficient amount to substantially solubilize the atleast one active agent in the composition. The term “substantiallysoluble” means that at least 95% of the active agent has beensolubilized, i.e., 5% or less of the active agent is present in a solidstate. In one or more embodiments, the concentration of the at least onepotent solvent is more than about 40% of the at least one solvent of thecomposition; or even more than about 60%.

Non-limiting examples of pairs of active agent and potent solventinclude: Betamethasone valerate: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in glycofurol; Hydrocortisone butyrate:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol; Metronidazole: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in dimethyl isosrbide; Ketoconazole:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, propylene glycol and dimethyl isosrbide; Mupirocin:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol andpolyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidalanti-inflammatory agent: Practically insoluble in mineral oil (<0.001%);soluble in propylene glycol: 0.3 mg/mL; and in PEG 400: 3.7 mg/mL; andProgesterone: Practically insoluble in mineral oil (<0.001%); soluble inPEG 400: 15.3 mg/mL.

A non-limiting exemplary list of solvents that can be considered aspotent solvents includes polyethylene glycol, propylene glycol, hexyleneglycol, butaneediols and isomers thereof, glycerol, benzyl alcohol,DMSO, ethyl oleate, ethyl caprylate, diisopropyl adipate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, isosorbide derivatives, such as dimethylisosorbide, glycofurol and ethoxydiglycol (transcutol) and laurocapram.

In another aspect, the present invention provides a method of designinga stable petrolatum foamable composition by selecting at least oneactive agent; and identifying a solvent that solubilizes the activeagent substantially better than mineral oil or petrolatum, for example,solubilizes the active agent 5-fold better or even 10-fold better than ahydrocarbon solvent such as mineral oil or petrolatum. The method mayfurther include adjusting the type and concentration of surfactant andgelling agent to provide a foamable composition.

In another aspect, the active agent has a degree of solubility insolvent, in petrolatum, in the emulsion or a phase thereof and a potentsolvent is used to increase the solubility, in one or both phases, inthe interphase or in the foam.

In another aspect, the active agent has a limited degree of solubilityin solvent, in petrolatum, in the emulsion or a phase thereof and apotent solvent is used to increase the solubility, in one or bothphases, in the interphase or in the foam.

The use of a potent solvent in a foam composition provides an improvedmethod of delivering poorly soluble therapeutic agents to a target area.It is known that low drug solubility results in poor bioavailability,leading to decreased effectiveness of treatment. Foam compositions, forwhich the solvent includes a potent solvent, increase the levels of theactive agent in solution and thus, provide high delivery and improvedtherapy.

Potent solvents, as defined herein, are usually liquid. Formulationscomprising potent solvents and active agents are generallydisadvantageous as therapeutics, since their usage involves unwanteddripping and inconvenient method of application; resulting in inadequatedosing. Surprisingly, the foams, which are drip-free, provide a superiorvehicle for such active agents, enabling convenient usage and accurateeffective dosing.

In one or more embodiments the present invention the foamablepharmaceutical composition may additionally include a potent solvent ora mixture of two or more of the above solvents selected from the groupof hydrophobic solvents, silicone oils, emollients, polar solvents andpotent solvents in an appropriate proportion as would be appreciated toa person skilled in the art and preferably in relatively small amounts.

Polymeric Agent

In one or more embodiments, the foamable composition contains apolymeric agent. The polymeric agent serves to stabilize the foamcomposition and to control drug residence in the target organ.

In one or more specific non limiting embodiments, the polymeric agent isASOS, carboxymethyl cellulose/microcrystalline cellulose, Arlacel 2121,or methocel and xantham gum.

More exemplary polymeric agents are classified below in a non-limitingmanner. In certain cases, a given polymer can belong to more than one ofthe classes provided below.

In one or more embodiments, the composition includes a gelling agent. Agelling agent controls the residence of a therapeutic composition in thetarget site of treatment by increasing the viscosity of the composition,thereby limiting the rate of its clearance from the site. Many gellingagents are known in the art to possess mucoadhesive properties.

The gelling agent can be a natural gelling agent, a synthetic gellingagent and an inorganic gelling agent. Exemplary gelling agents that canbe used in accordance with one or more embodiments include, for example,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, starch, chemically modified starches and the like, semi-syntheticpolymeric materials such as cellulose ethers (e.g. hydroxyethylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxypropylmethyl cellulose, hydroxyethylcarboxymethylcellulose,carboxymethylcellulose and carboxymethylhydroxyethylcellulose), guargum, hydroxypropyl guar gum, soluble starch, cationic celluloses,cationic guars, and the like, and synthetic polymeric materials, such ascarboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,polyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers and the like. Mixtures of the above compounds are alsocontemplated.

Further exemplary gelling agents include the acrylic acid/ethyl acrylatecopolymers and the carboxyvinyl polymers. Non-limiting examples includeCarbopol® 934, Carbopol® 940, Carbopol® 950, Carbopol® 980, Carbopol®951 and Carbopol® 981. Such agents can function as stabalisers in one ormore embodiments and as delivery enhancers in one or more otherembodiments.

Yet, in other embodiments, the gelling agent includes inorganic gellingagents, such as silicone dioxide (fumed silica).

Mucoadhesive/bioadhesion has been defined as the attachment of syntheticor biological macromolecules to a biological tissue. Mucoadhesive agentsare a class of polymeric biomaterials that exhibit the basiccharacteristic of a hydrogel, i.e. swell by absorbing water andinteracting by means of adhesion with the mucous that covers epithelia.Compositions may contain a mucoadhesive macromolecule or polymer in anamount sufficient to confer or partially to confer bioadhesiveproperties, although these substances may by their nature, increase thetackiness of a composition so this will be taken into account inpreparing compositions. The bioadhesive macromolecule can enhancedelivery of biologically active agents on or through the target surface.The mucoadhesive macromolecule may be selected from acidic syntheticpolymers, preferably having an acidic group per four repeating ormonomeric subunit moieties, such as poly(acrylic)- and/orpoly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinylether/maleic anhydride) copolymer, and their mixtures and copolymers;acidic synthetically modified natural polymers, such ascarboxymethylcellulose (CMC); neutral synthetically modified naturalpolymers, such as (hydroxypropyl)methylcellulose; basic amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth,and karaya gum; and neutral synthetic polymers, such as polyvinylalcohol or their mixtures. An additional group of mucoadhesive polymersincludes natural and chemically modified cyclodextrin, especiallyhydroxypropyl-β-cyclodextrin. Such polymers may be present as freeacids, bases, or salts, usually in a final concentration of about 0.01%to about 0.5% by weight. Many mucoadhesive agents are known in the artto also possess gelling properties.

In one or more embodiments, the polymeric agent contains a film-formingcomponent, although these substances may also by their nature, increasethe tackiness of a composition so this will be taken into account inpreparing compositions. The film-forming component may include awater-insoluble alkyl cellulose or hydroxyalkyl cellulose. Exemplaryalkyl cellulose or hydroxyalkyl cellulose polymers include ethylcellulose, propyl cellulose, butyl cellulose, cellulose acetate,hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethylcellulose, alone or in combination. In addition, a plasticizer or across-linking agent may be used to modify the polymer's characteristics.For example, esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asoleic and myristyl acid may be used in combination with the cellulosederivative.

In one or more embodiments, the polymeric agent includes a phase changepolymer, which alters the composition behavior from fluid-like prior toadministration to solid-like upon contact with the target mucosalsurface. Such phase change results from external stimuli, such aschanges in temperature or pH and exposure to specific ions (e.g., Ca²⁺).Non-limiting examples of phase change polymers includepoly(N-isopropylamide) and Poloxamer 407®.

The polymeric agent is present in an amount in the range of about 0.01%to about 5.0% by weight of the foam composition. In one or moreembodiments, it is typically less than about 1 wt % of the foamablecomposition.

Preferably, a therapeutically effective foam adjuvant is included in thefoamable compositions to increase the foaming capacity of surfactantsand/or to stabilize the foam. In one or more embodiments, the foamadjuvant agent includes fatty alcohols having 15 or more carbons intheir carbon chain, such as cetyl alcohol and stearyl alcohol (ormixtures thereof). Other examples of fatty alcohols are myristyl alcohol(C14), arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol(C30), as well as alcohols with longer carbon chains (up to C50). Fattyalcohols, derived from beeswax and including a mixture of alcohols, amajority of which has at least 20 carbon atoms in their carbon chain,are especially well suited as foam adjuvant agents. The amount of thefatty alcohol required to support the foam system is inversely relatedto the length of its carbon chains. Foam adjuvants, as defined hereinare also useful in facilitating improved spreadability and absorption ofthe composition.

In one or more embodiments, the foam adjuvant agent includes fatty acidshaving 16 or more carbons in their carbon chain, such as hexadecanoicacid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22),octacosanoic acid (C28), as well as fatty acids with longer carbonchains (up to C50), or mixtures thereof. As for fatty alcohols, theamount of fatty acids required to support the foam system is inverselyrelated to the length of its carbon chain.

In one or more embodiments, a combination of a fatty acid and a fattyester is employed.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have a double bond. A further class of foam adjuvant agent includesa branched fatty alcohol or fatty acid. The carbon chain of the fattyacid or fatty alcohol also can be substituted with a hydroxyl group,such as 12-hydroxy stearic acid.

A property of the fatty alcohols and fatty acids used in context of thecomposition is related to their therapeutic properties per se. Longchain saturated and mono unsaturated fatty alcohols, e.g., stearylalcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol(docosanol) have been reported to possess antiviral, antiinfective,antiproliferative and anti-inflammatory properties (see, U.S. Pat. No.4,874,794). Longer chain fatty alcohols, e.g., tetracosanol,hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are alsoknown for their metabolism modifying properties and tissue energizingproperties. Long chain fatty acids have also been reported to possessanti-infective characteristics.

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, spheres,microspheres, nanocapsules, nanospheres, liposomes, niosomes, polymermatrix, nanocrystals or microsponges.

The composition may further optionally include a variety of formulationexcipients, which are added in order to fine-tune the consistency of theformulation, protect the formulation components from degradation andoxidation and modify their consistency. Such excipients may be selected,for example, from stabilizing agents, antioxidants, humectants,moisturizers, preservatives, colorant and odorant agents and otherformulation components, used in the art of formulation.

Propellants

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable carrier. The propellant makes up about 3% to about 25% (w/w) ofthe foamable carrier or composition. Examples of suitable propellantsinclude volatile hydrocarbons such as butane, propane, isobutane, andfluorocarbon gases or mixtures thereof. In an embodiment the propellantis 1681, which is a mixture of three gas propellants propane, isobuteneand butane. In another embodiment it is AP 70, which is a mixture ofpropane, isobutene and butane with a higher pressure. In somecircumstances the propellant may be up to 35%. The total compositionincluding propellant, foamable compositions and optional ingredients isreferred to as the foamable composition. However, for the purposes ofcalculating the percentage of each component and thereby the amountpresent in the resultant foam the propellant is not included in the 100%but is instead added to the 100% since the propellant is essentiallydischarged into the atmosphere upon expulsion of the formulation.

Non-Flammable Stable Foam Compositions

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMCs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect include propellantsmade by DuPont under the registered trademark Dymel, such as 1,1,1,2tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane(Dymel 227). HFCs possess Ozone Depletion Potential of 0.00 and thus,they are allowed for use as propellant in aerosol products.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butane or mixtures ofhydrocarbon propellants such as propane, isobutane and butane.

Additional Components

In an embodiment, a composition includes one or more additionalcomponents. Such additional components include but are not limited toanti perspirants, anti-static agents, buffering agents, bulking agents,conservational agents, chelating agents, cleansers, colorants,conditioners, deodorants, diluents, dyes, emollients, fragrances, hairconditioners, humectants, pearlescent aids, perfuming agents, permeationenhancers, pH-adjusting agents, preservatives, protectants, skinpenetration enhancers, softeners, solubilizers, sunscreens, sun blockingagents, sunless tanning agents, viscosity modifiers, ionization agents,and antioxidants like flavonoids and phenolics. As is known to oneskilled in the art, in some instances a specific additional componentmay have more than one activity, function or effect.

In an embodiment, the additional component is a pH adjusting agent or abuffering agent. Suitable buffering agents include but are not limitedto acetic acid, adipic acid, calcium hydroxide, citric acid, glycine,hydrochloric acid, lactic acid, magnesium aluminometasilicates,phosphoric acid, sodium carbonate, sodium citrate, sodium hydroxide,sorbic acid, succinic acid, tartaric acid, and derivatives, salts andmixtures thereof.

Sodium Metabisulfite (Disodium Metabisulfite) and Derivatives

Sodium metabisulfite is used as an antioxidant in (primarily acidic)pharmaceutical formulations, at concentrations of 0.01-1.0% w/v.,preparations and can also be used as a preservative having someantimicrobial activity at though for alkaline preparations, sodiumsulfite is usually preferred

Active Agents

It is to be understood that the active agents useful herein can in someinstances provide more than one benefit or operate via more than onemode of action. Therefore, classifications herein are made for the sakeof convenience and are not intended to limit the active agent to thatparticular application or applications listed.

The composition comprises an active agent that provides therapeutic orcosmetic activity.

Non-limiting examples of active agents include an anti-infective, anantibiotic, an antibacterial agent, an antifungal agent, an antiviralagent, an antiparasitic agent, a steroidal anti-inflammatory agent, anonsteroidal anti-inflammatory agent, an immunosuppressive agent, animmunomodulator, an immunoregulating agent, a hormonal agent, a steroid,a vasoactive agent, a vasoconstrictor, a vasodilator, vitamin A, avitamin A derivative, a retinoid, vitamin B, a vitamin B derivative,vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative,vitamin E, a vitamin E derivative, alpha-tocopheryl polyethylene glycolsuccinate, vitamin F, a vitamin F derivative, vitamin K, a vitamin Kderivative, a wound healing agent, a burn healing agent, a disinfectant,an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lacticacid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, aneuropeptide, an allergen, an immunogenic substance, a haptene, anoxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid,sebacic acid, adipic acid, fumaric acid, an insecticide, anantiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,titanium dioxide, zinc oxide, zirconium oxide, iron oxide), siliconeoxide, talc, an anti-acne agent, a skin whitening agent, a self tanningagent, an anti-cellulite agent, a skin protective agent, a maskingagent, an anti-wart agent, a refatting agent, a lubricating agent andmixtures thereof at any proportion. The concentration of the activeagent can be adapted to exert a therapeutic effect on a disease whenapplied to an afflicted area.

In one or more embodiments the active agent may be vitamin D or aderivative such as calcipotriol or calcitriol. In one or more otherembodiments the vitamin D or derivative is used in combination with asteroid. Due to the different environmental requirements of the twotypes of API's it is very difficult to produce formulations that areboth chemically and physically stable. In certain embodiments there areprovided chemically and physically stable formulations containing one orboth active agents. Nevertheless, in certain other preferred embodimentsthe active agents are in separate formulations and are delivered bymeans of a multichamber or dual chamber device. Alternatively they canbe expelled manually simultaneously or consecutively from two separatecanisters directed to the same target site.

In one or more embodiments the active agent may be an extract ortincture of one or more beneficial agents that have beneficialproperties, for example, when applied to the skin, a body surface, abody cavity or a mucosal surface. The extract can be, for example,alcoholic, hydroalcoholic, propelyne glycol, glycerine, dry, press,cold, hot, liquid carbon dioxide, oil or other process known in the art.The extract or tincture may comprise of substances of animal, plant,(such as herb, fruit, vegetable) mineral or other origin. Nonlimitingexamples are proteins, polypepeptides, sugars, hyularonic acid, and coaltar. Herbal extracts may be from any known therapeutic herb, as listedfor example in Herbal Medicines, London: Pharmaceutical Press ElectronicVersion 2006 or in the American Herbal Association electronicpublication Herbal gram or in German Commission E., such as, angelica,calendula, celery, coltsfoot, comfrey, dandelion, jamaica dogwood, kava,marshmallow, prickly ash, northern prickly ash, southern senna,valerian, agrimony, aloe vera, alfalfa, artichoke, avens, bayberry,bloodroot, blue flag, bogbean, boldo, boneset, broom, buchu, burdock,burnet, calamus, calendula, cascara, centaury, cereus, chamomile, germanchamomile, roman chamomile, cinnamon, clivers, cohosh, black, cohosh,blue, cola, corn silk, couchgrass, cowslip, damiana, devil's claw,drosera, echinacea, elder, elecampane, euphorbia, eyebright, figwort,frangula, fucus, fumitory, garlic, golden seal, gravel root, ground ivy,guaiacum, hawthorn, holy thistle, hops, horehound black, horehoundwhite, horse chestnut hydrangea, ispaghula, juniper, lady's lipper,liferoot, lime flower, liquorice, lobelia, mate, meadowsweet, mistletoe,motherwort, myrrh, nettle, parsley, parsley piert, passionflower,pennyroyal, pilewort, plantain, pleurisy root, pokeroot, poplar,pulsatilla, queen's delight, raspberry, red clover, rosemary, sage,sarsaparilla, sassafras, scullcap, senega, shepherd's purse, skunkcabbage, slippery elm, squill, St. John's wort, stone root, tansy,thyme, uva-ursi, vervain, wild carrot, wild lettuce, willow, witchhazel, yarrow and yellow dock. The extract may contain, for example, anaqueous, polar, hydrophobic or potent solvent as will be appreciated bya person of ordinary skill in the art.

In one or more embodiments, the active agent is an anti-infective agent,selected from an antibiotic agent, an antibacterial agent, ananti-fungal agent, an anti-viral agent and an anti-parasite agent.

The antibacterial drug can be active against gram positive andgram-negative bacteria, protozoa, aerobic bacteria and anaerobic ones.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting of beta-lactam antibiotics, synthetic andsemi-synthetic penicillin's, aminoglycosides, ansa-type antibiotics,anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides,antibiotic nucleosides, antibiotic peptides, antibiotic polyenes,antibiotic polyethers, quinolones, fluoroquinolnes, antibiotic steroids,cyclosporines, sulfonamides, tetracycline, chloramphenicol, dicarboxylicacids, such as azelaic acid, salicylates, antibiotic metals, oxidizingagents, substances that release free radicals and/or active oxygen,cationic antimicrobial agents, quaternary ammonium compounds,biguanides, triguanides, bisbiguanides and analogs and polymers thereofand naturally occurring antibiotic compounds.

Additional antibacterial agents, which are non-specific, include strongoxidants and free radical liberating compounds, such as hydrogenperoxide, bleaching agents (e.g., sodium, calcium or magnesiumhypochloride and the like), iodine, chlorohexidine and benzoyl peroxide.

The antifungal agent can be an azole compound. Exemplary azole compoundsinclude azoles selected from the group consisting of azoles, diazoles,triazoles, miconazole, ketoconazole, clotrimazole, econazole,mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole,oxiconazole, sertaconazole, sulconazole, thiabendazole, tiaconazole,fluconazole, itraconazole, ravuconazole and posaconazole.

Additional exemplary antifungal agents include griseofulvin, ciclopirox,amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine(5FC) and any combination thereof at a therapeutically effectiveconcentration.

In one or more embodiments, the active agent is an anti-viral agent. Anyknown antiviral agent, in a therapeutically effective concentration, canbe incorporated in the foam composition. Exemplary antiviral agentsinclude, but not limited to, acyclovir, famciclovir, gancyclovir,valganciclovir and abacavir.

In another embodiment according to the present invention, the activeagent is an anti-inflammatory or anti-allergic agent. Anti-inflammatoryagents can be selected from the group of corticosteroids, non-steroidalanti-inflammatory drugs (NSAIDs), anti-histamines, immunosuppressantagents, immunomodulators; and any combination thereof at atherapeutically effective concentration.

Non-limiting examples of corticosteroids include hydrocortisone,hydrocortisone acetate, desonide, betamethasone valerate,clobetasone-17-butyrate, flucinonide, fluocinolone acetonide,alcometasone dipropionate, mometasone furoate, prednicarbate,triamcinolone acetonide, betamethasone-17-benzoate, methylprednisoloneaceponate, betamethasone dipropionate, halcinonide, triamcinoloneacetonide, halobetasol and clobetasol-17-propionate.

A second class of anti-inflammatory agents, which is useful in the foam,includes the nonsteroidal anti-inflammatory agents (NSAIDs). The varietyof compounds encompassed by this group is well known to those skilled inthe art. Specific non-steroidal anti-inflammatory agents useful in thecomposition invention include, but are not limited to, oxicams, such aspiroxicam, isoxicam, tenoxicam, sudoxicam; salicylates, such assalicylic acid, ethyl salicylate, methyl salycilate, aspirin, disalcid,benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;scetic acid derivatives, such as diclofenac, fenclofenac, indomethacin,sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin,acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, andketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic,niflumic, and tolfenamic acids; propionic acid derivatives, such asibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen,fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; andpyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone,azapropazone, and trimethazone.

Any further steroidal and nonsteroidal compounds, having the capacity toprevent, alleviate the symptoms of, treat or cure inflammationprocesses, are generally included, as possible anti-inflammatory agents,according to the present invention.

Antiallergic active agents include antihistamine compounds, including,in a non limiting manner, thylenediamines, such as pyrilamine(mepyramine), antazoline and methapyrilene; tripelennaminephenothiazines, such as promethazine, methdilazine and trimeprazine;ethanolamines, such as diphenhydramine, bromodiphenhydramine,carbinoxamine, clemastine, dimenhydrinate, diphenylpyraline, doxylamineand phenyltoxamine; piperazines, such as cyclizine, buclizine,chlorcyclizine, hydroxyzine, meclizine and thiethylperazine;alkylamines, such as brompheniramine, pyrrobutamin, desbrompheniramine,tripolidine, dexchlorpherniramine, chlorpheniramine; dimethindene andpheniramine; and piperidines, such as cyproheptadine and azatadine.These active agents, as well as additional antihistamines can also beincorporated in the composition.

The composition may also comprise an anti-inflammatory or antiallergicagent, wherein said agent reduces the occurrence of pro-inflammatorycytokines or inhibits the effect of pro-inflammatory cytokines.

Immunosuppressant agents, immunoregulating agents and immunomodulatorsare chemically or biologically derived agents that modify the immuneresponse or the functioning of the immune system (as by the stimulationof antibody formation or the inhibition of white blood cell activity).Immunosuppressant agents and immunomodulators include, among otheroptions, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimodand imiquimod.

In one or more embodiments, the active agent is a topical anesthetic.Examples of topical anesthetic drugs include, but not limited to,benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine,etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine,cocaine, ketamine, pramoxine, and phenol. Mixtures of such anestheticagents may be synergistically beneficial.

In one or more embodiments, the active agent is a “keratolyticallyactive agent.” The term “keratolytically active agent” refers herein toa compound, which loosens and removes the stratum corneum of the skin,or alters the structure of the keratin layers of the skin.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. Dihydroxy benzeneand derivatives thereof have been recognized as potent keratolyticagents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are usedin anti-acne preparations. Hydroquinone (p-dihydroxybenzene), besidesits anti-pigmentation properties, is also keratolytic.

Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid,retinol and retinal are another preferred class of keratolyticallyactive agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as Salicylic acid(o-hydroxybenzoic acid) and its salts and pharmaceutically acceptablederivatives, which typically possess anti-inflammatory, as well askeratolytic, activity. Yet, another class of preferred keratolyticallyactive agents includes urea and its derivatives.

In one or more embodiments, the active agent is a retinoid. Retinoidsinclude, for example, retinol, retinal, all-trans retinoic acid andderivatives, isomers and analogs thereof. Etretinate, actiretin,isotretinoin, adapalene and tazarotene are further examples of saidretinoid isomers and analogs.

In one or more embodiments, the active agent is a vitamin D₃ analoguesuch as calcipotriol, tacalcitol, maxacalcitol, and calcitriol withcalcipotriol being especially preferred. Vitamin D₃ analogues andderivatives are known to degrade at low pH levels. The waterlesscompositions can protect against or retard such degredation. In certainembodiments where the active agent is vitamin D₃ or an analogue or aderivative thereof, and there is a concern that there are some potentialresidues which could effect the agent in the composition or followingapplication to the skin or a body cavity could cause breakdown aneutralizing or stabilizing agent might additionally be added whichcould be a suitable pH adjuster or buffer. Note where calcipotriol and asteroid like betmethasone diproprionate are in the same composition thewaterless compositions are ideal to protect from degradation. In anaqueous environment they have opposing pH requirements for stabilitywith the steroid favoring an acidic environment and the vitamin favoringa basic environment.

In one or more embodiments, the active agent is an insecticide or aninsect repellent agent.

In one or more embodiments, the active agent is an anti cancer agent.

In one or more embodiments, the active agent is a photodynamic therapy(PDT) agent. By way of example, such PDT agents can be modifiedporphyrins, chlorins, bacteriochlorins, phthalocyanines,naphthalocyanines, pheophorbides, purpurins, m-THPC, mono-L-aspartylchlorin e6, bacteriochlorins, phthalocyanines, benzoporphyrinderivatives, as well as photosensitizer precursors, such asaminolevulinic acid (ALA).

In one or more embodiments, the active agent is an agent useful in thetreatment of burns, wounds, cuts and ulcers. The foam compositions maycomprise a combination of anti-infective agents (against bacteria, fungiand/or viruses), anti-inflammatory agents (steroidal and/or NSAIDs) andpain relieving components.

In one or more embodiments, the active agent can also be used as anabsorption and bioavailability enhancer for other drugs and vitamins,for example TPGS that forms its own micelles can aid e.g. amprenavir andvitamin D respectively.

In one or more embodiments the active agent has some degree ofsolubility in water. By the phrase some degree of solubility it isunderstood to include API's that are described by the US or EuropeanPharmacopoeia as being slightly soluble, sparingly soluble, soluble,freely soluble or very soluble. Both describe the approximate ranges ofparts of solvent (volume) required for 1 part (per gram) of solute asless than 1 for very soluble; from 1-10; for freely soluble, from 10-30for soluble; from 30 to 100 for sparingly soluble; and from 100 to 1000for slightly soluble. Additionally, the phrase may include the termspartly soluble and miscible. Non limiting examples of substances thathave some degree of solubility in water are acyclovir, azelaic acid,allantoin, ammonium lactate, benzoyl peroxide, caffeine, calcipotriol,ciclopirox olamine, clindamycin hydrochloride, clindamycin phosphate,clindamycin palmitate hydrochloride, coal tar, cyanocobalamine,diclofenac sodium, gentamycin sulphate, lactic acid, glycyrrhizinicacid, map (magnesium ascorbyl phosphate), minoxidil, mupirocin,salicylic acid, terbinafine, urea, fusidic acid, a hydrocortisone,hydrocortisone sodium phosphate, hydrocortisone sodium succinate, aclobetasol, a halobetasol, a batamethsone; halobetasol andclobetasol-17-propionate or -17-butyrate; ketoconazole, lidocainehydrochloride, metronidazole, tetracycline, tetracycline hydrochloride,meclocycline sulfosalicylate, resorcinol, chloramphenicol, erythromycin,acriflavinium monochloride, ethacridine lactate, dibrompropamidineisetionate, chlorhexidine acetate, chlorhexidine gluconate,chlorhexidine hydrochloride, hexamidine isetionate, phenol,povidone-iodine, dequalinium chloride, hydroxyquinoline sulfate,potassium hydroxyquinoline sulphate, benzalkonium chloride, cetrimoniumbromide, cetylpyridinium chloride, cetrimide, phenylmercuric acetate,phenylmercuric borate, mercuric chloride, silver nitrate, potassiumpermanganate, tosylchloramide sodium, prednisolone sodium phosphate,betamethasone sodium phosphate, demeclocycline, demeclocyclinehydrochloride, chlortetracycline hydrochloride, oxytetracyclinehydrochloride, neomycin sulfate, bacitracin zinc, gentamicin sulphate,amikacin, amikacin sulphate, sulfathiazole sodium, mafenide acetate,idoxuridine, fumaric acid, mepyramine maleate, tripelennaminehydrochloride, promethazine hydrochloride, dimetindene maleate,diphenhydramine hydrochloride, cinchocaine hydrochloride, oxybuprocainehydrochloride, benzocaine, tetracaine hydrochloride, pramoxinehydrochloride, panthenol, dexpanthenol, calcium pantothenate, hyaluronicacid, trypsin, aminobenzoic acid, methylrosanilinium chloride, sodiumbutyl hydroxybenzoate, sodium ethyl hydroxybenzoate, sodium methylhydroxybenzoate, sodium propyl hydroxybenzoate, flucytosine andfluconazole.

In one or more embodiments the active agent has a limited degree ofsolubility in water. By a limited degree of solubility it is understoodto include API's that are described by the US or European Pharmacopoeiaas being very slightly soluble. The approximate range of parts ofsolvent (volume) required for 1 part (per gram) of solute is from 1000to 10000 for very slightly soluble.

In one or more embodiments the active agent has some degree ofsolubility in an petrolatum emollient. So any agent that by its natureis hydrophobic may qualify, such as permethrin and tetracaine.

In one or more embodiments the active agent has some degree ofsolubility in a composition in one or more of the water phase, the oilphase, or the interphase or the foam. For example, beamethasone valeratehas been stated to be practically insoluble in water. However, it hasbeen surprisingly found that it is soluble in the water phase of afoamable composition in a pharmaceutically effective amount for topicalapplication.

The foam compositions, with or without further active ingredients, aresuitable for the further application as “cosmeceutical” preparation(cosmetic products with therapeutic benefit), to treat “cosmetic” skindisorders, such as aging skin, wrinkles, hyperpigmentation (melasma,chloasma, freckles, etc.), scaly skin and other skin undesirableproperties.

Any cosmetically active agent is considered an active agent in thecontext. The CTFA Cosmetic Ingredient Handbook describes a wide varietyof non-limiting cosmetic and pharmaceutical ingredients commonly used inthe skin care industry, which are suitable for use in the compositions.Examples of these ingredient classes include: abrasives, absorbents,aesthetic components such as fragrances, pigments, colorings/colorants,essential oils, astringents, etc. (e.g., clove oil, menthol, camphor,eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate),anti-acne agents, anti-caking agents, antifoaming agents, anti-microbialagents (e.g., iodopropyl butylcarbamate), antioxidants, binders,biological additives, buffering agents, bulking agents, chelatingagents, chemical additives, colorants, cosmetic astringents, cosmeticbiocides, denaturants, drug astringents, external analgesics, filmformers or materials, e.g., polymers, for aiding the film-formingproperties and substantivity of the composition (e.g., copolymer ofeicosene and vinyl pyrrolidone), opacifying agents, pH adjusters,propellants, reducing agents, sequestrants, skin bleaching andlightening agents (e.g., hydroquinone, kojic acid, ascorbic acid,magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioningagents (e.g., humectants, moisturizers, etc.), skin soothing and/orhealing agents (e.g., panthenol and derivatives (e.g., ethyl panthenol),aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol,and dipotassium glycyrrhizinate), skin treating agents, and vitamins andderivatives thereof.

In one or more embodiments, the active agent is an agent useful in thetreatment of acne, wrinkles and scars. Examples of useful anti-acneactives include resorcinol, sulfur, salicylic acid and salicylates,alpha-hydroxy acids, nonsteroidal anti-inflammatory agents, benzoylperoxide, retinoic acid, isoretinoic acid and other retinoid compounds,adapalene, tazarotene, azelaic acid and azelaic acid derivatives,antibiotic agents, such as erythromycin and clyndamycin, zinc salts andcomplexes, and combinations thereof, in a therapeutically effectiveconcentration. Exemplary anti-wrinkle/anti-atrophy active agentssuitable for use in the compositions include sulfur-containing D and Lamino acids and their derivatives and salts, particularly the N-acetylderivatives; thiols; hydroxy acids (e.g., alpha-hydroxy acids such aslactic acid and glycolic acid and their derivatives and salts; orbeta-hydroxy acids such as salicylic acid and salicylic acid salts andderivatives), urea, hyaluronic acid, phytic acid, lipoic acid;lysophosphatidic acid, skin peel agents (e.g., phenol, resorcinol andthe like), vitamin B3 compounds (e.g., niacinamide, nicotinic acid andnicotinic acid salts and esters, including non-vasodilating esters ofnicotinic acid (such as tocopheryl nicotinate), nicotinyl amino acids,nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide andniacinamide N-oxide), vitamin B5 and retinoids (e.g., retinol, retinal,retinoic acid, retinyl acetate, retinyl palmitate, retinyl ascorbate).In the case of dry, scaly skin (xerosis) and ichthyosis such agents canalleviate the symptoms by temporary relief of itching associated withthese conditions.

In one or more embodiments, the active agent is an anti-oxidant or aradical scavenger. Anti-oxidants/radical scavengers such as ascorbicacid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbicacid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbylphosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherolsorbate, tocopherol acetate, other esters of tocopherol, butylatedhydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid andits alkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts maybe used.

It is further pointed out that polyunsaturated fatty acids, containingomega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA)) are beneficial in the treatment of psoriasisand other skin inflammation conditions. Likewise, emollients andsilicone oils exert moisture-retaining and skin protective effects onthe skin. Thus, in a preferred embodiment, a skin protective foam isprovided, wherein the hydrophobic carrier comprises in full or in part,an organic liquid selected from the group consisting of emollients,silicone oil and oils rich in unsaturated fatty acids.

In one or more embodiments, the active agent is a self-tanning activeAgent, such as dihydroxyacetone.

According to another embodiment, the active agent comprises solid matteror particulate matter, i.e., material that is not soluble in the liquidcarrier composition of the foamable composition. For definitionpurposes, solid matter shall mean material that is not soluble in thefoamable composition more than 10% of the concentration intended to beincluded in said foamable composition. By way of example, the followingclasses of solid matter substances are presented: metallic oxides, suchas titanium dioxide, zinc oxide, zirconium oxide, iron oxide; siliconcontaining materials such as silicone oxide and talc; carbon, forexample in the form of amorphous carbon or graphite; insoluble oxidizingagents, such as benzoyl peroxide, calcium and magnesium hypochlorite;metallic Silver; cosmetic scrub materials, including, for example mealsof strawberry seeds, raspberry seeds, apricot seeds, sweet almond,cranberry seeds; and pigments.

In an embodiment the solid is substantially uniformly dispersed as asuspension in the composition, wherein the composition is formulated sothat the resultant foam when applied topically to a target will form aneffective barrier and the composition does not comprise a non propellantorganic cosolvent.

According to certain embodiments, the active agent is selected from thegroup of solvent, surface active agent, foam adjuvant and gelling agent,which are, on a case-by-case basis, known to possess a therapeuticbenefit.

In one or more embodiments at least one or at least two active agentsare included in the composition.

Whenever there is reference to an active agent and or derivatives thereference includes, derivatives, conjugates, analogues, prodrugs,chelates, complexes, ions, isomers, enantimers, and salts thereof.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier is very easy to use. When applied onto the afflicted bodysurface of mammals, i.e., humans or animals, it is in a foam state,allowing free application without spillage. Upon further application ofa mechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

The foamable composition can be in the state of (1) solutions; (2) areadily dispersible suspension; or (3) an emulsion. It is stable, havingan acceptable shelf life of a year, or at least two years at ambienttemperature, as revealed in accelerated stability tests. Polar solvents,hydrophobic carriers and propellants, which are a mixture of lowmolecular weight hydrocarbons, tend to impair the stability of emulsionsand to interfere with the formation of a stable foam upon release from apressurized container. It has been observed, however, that the foamablecompositions according to the present invention are surprisingly stable.Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing semi-solid hydrophobicsolvents, e.g., white petrolatum, as the main ingredients of the oilphase of the emulsion, exhibit high viscosity and reduced or poorflowability and are not ideal candidates for a foamable composition. Ithas been found that despite the aforesaid in the compositions s theproduce foams, which are surprisingly soft, or with improved stability.

Where the petrolatum emollient is provided in large quantitiessufficient to produce an effective occlusion the foam can act as abarrier to water soluble irritants and air borne bacteria whilst alsoproviding a vehicle for water soluble active agents. However, there is apotential downside of anaerobic bacteria growing under the barrier.Depending on the nature of the emulsion formulation an petrolatumemollient can aid API transport through the skin or retard penetrationprolonging thereby its action. Accordingly a pharmaceutical formulationfor example with petrolatum can be designed to improve or prolongdelivery as is required as will be appreciated by a person skilled inthe art.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal. Achieving G orE, where petrolatum. a heavy, greasy, tacky substance, is the main ormajor component is a challenge and achievement. As a consequence of thehigh levels of petrolatum and its nature, the density of the resultantfoams can be significantly higher than with non or low petrolatum foams.With high petrolatum a density of the order of about 0.5 g to about 0.4g is acceptable. Nevertheless, in certain other embodiments relativelylow density petrolatum foams can be achieved having a density belowabout 0.4 g and preferably with a density of less than about 0.2 g.

A further aspect of the foam is breakability. The breakable foam isthermally stable, yet breaks under sheer force. Sheer-force breakabilityof the foam is clearly advantageous over thermally induced breakability.Thermally sensitive foams immediately collapse upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

In one or more embodiments there is provided a composition, wherein thefoam demonstrates at least eighteen of the following properties:

-   -   a) a foam quality of 5-6;    -   b) a color of white to off-white; or a yellowish color:    -   c) no odor or faint odor; or substantially masked odor;    -   d) a foam quality of 5-6 after one freeze-thaw cycle;    -   e) a foam quality of 5-6 after two freeze-thaw cycles;    -   f) a foam quality of 5-6 after three freeze-thaw cycles;    -   g) a foam quality of 5-6 after four freeze-thaw cycles;    -   h) a foam quality of 5-6 after about 3 weeks' storage at 30° C.;    -   i) a foam quality of 5-6 after about 3 weeks' storage at 40° C.;    -   j) a foam quality of 5-6 after about 3 months' storage at 30°        C.;    -   k) a foam quality of 5-6 after about 3 months' storage at 40°        C.;    -   l) a collapse time of more than 50 seconds;    -   m) a collapse time of more than 120 seconds; and    -   n) a collapse time of more than 180 seconds;    -   o) a collapse time of more than 300 seconds;    -   p) a foam hardness in the range of about 5 g to about 100 g;    -   q) a foam hardness in the range of about 15 g to about 55 g;    -   r) a foam hardness in the range of about 30 g to about 85 g;    -   s) a density of less than 0.5 g;    -   t) a density of less than 0.3 g;    -   u) a density of less than 0.2 g;    -   v) a foam corneometer value of at least 50 after washing a        formulation applied to the skin; and    -   w) an average focus group score of 60 or more.

In a preferred embodiment it demonstrates one or more of the following:nineteen; twenty; twenty one; twenty two properties and in a morepreferred embodiment it demonstrates all of the properties.

In one or more embodiments there is provided a composition, wherein thefoam provides at least two of the following traits:

-   -   a) increased solubility of the active agent;    -   b) increased delivery of the active agent;    -   c) the composition provides enhanced skin barrier build up;    -   d) the composition provides increased penetration of the active        agent whilst replenishing the skin;    -   e) the composition prolongs the delivery of the active agent        whilst replenishing the skin.

In one or more embodiments there is provided a composition, wherein thefoam provides at least two of the following traits:

-   -   a) the composition is able to at least partially solubilize the        active agent;    -   b) the composition is able to substantially solubilize the        active agent.    -   c) the active agent is at least partially soluble in petrolatum        or mixtures thereof;    -   d) the active agent is at least partially soluble in a solvent        substantially miscible in petrolatum or mixtures thereof    -   e) the active agent is at least partially soluble in a        hydrophilic solvent;    -   f) the active agent is at least partially soluble in an oil. the        active agent is at least partially soluble in a PPG alkyl eth        the active agent is insoluble or slightly soluble and is        distributed uniformly in the composition.

Dual Chamber

Dual and Multi Chamber devices and heads suitable for use with theformulations described herein where a first formulation is stored in afirst canister and a second formulation is stored in a second canisterare described in U.S. Pat. No. 6,305,578 entitled DEVICE FOR MIXING,FOAMING AND DISPENSING LIQUIDS FROM SEPARATE COMPRESSED-GAS CONTAINERSand in US Publication 2007-0069046 and entitled APPARATUS AND METHOD FORRELEASING A MEASURE OF CONTENT FROM A PLURALITY OF CONTAINERS all ofwhich are incorporated herein by reference in their entirety. Moreparticularly any of the devices and uses described are applicable hereinand are incorporated by reference.

In an embodiment the dual chamber device is as described in U.S. Pat.No. 6,305,578 for example,

a compressed gas container apparatus, having

-   -   at least two compressed gas containers, disposed side by side,        each for one foamable liquid product which contains a liquefied        propellant gas, wherein    -   both compressed gas containers are each provided with a valve,    -   both valves are actuatable in common by a top fitting, and    -   each valve is provided through the top fitting with a connecting        conduit,    -   the connecting conduits discharge into a mixing chamber, and    -   an expansion conduit adjoins the mixing chamber and on its end        has a foam dispensing opening, characterized in that    -   the connecting conduits and the mixing chamber have such small        cross-sectional areas that when a product is dispensed, the        products flowing through the connecting conduits) and the mixing        chamber remain in a liquid phase.

In an embodiment the dual dispenser head is as described in USPublication 2007-0069046 for example:

a dispenser head for use with a plurality of containers, comprising:

-   -   (a) an actuator, wherein the dispensing head is structured and        positioned to be an actuator or comprises an actuator button        disposed within the dispensing head to simultaneously actuate        the plurality of containers    -   (b) a flow guide comprising        -   (A) a plurality of flow conduits disposed within the flow            guide; and        -   (B) for each of the plurality of flow conduits,            -   (ii) an inlet through a wall of the flow guide                connecting with a flow conduit; and            -   (iii) an outlet from a flow conduit through a wall of                the flow guide;        -   (C) and for each of the plurality of inlets and containers,            a linker, each to link an inlet and a container to allow the            contents of the container upon actuation to pass through the            inlet and through the flow conduit to reach and pass through            the outlet;        -   (D) and wherein the flow guide is structured and positioned            to allow simultaneous flow communication between each of the            plurality of flow conduits and wherein the plurality of            outlets are structured and positioned to allow substantially            contemporaneously dispensing and/or combining of the content            from a plurality of containers external to the dispensing            head.

In one or more embodiments there is provided a kit comprising a dualchamber device or dual dispenser head, a first canister comprising afirst foamable formulation comprising a first API and a second canistercomprising a second foamable formulation comprising a second API whereineach canister is connectable to the said device or head. The firstfoamable formulation may be any of the stable petrolatum formulationsdescribed herein and the second foamable formulation may also be any ofthe stable petrolatum formulations described herein. In an embodimentthe first API is a steroid and the second API is a vitamin D derivativeand the each formulation is adapted to carry an effective amount ofsteroid and vitamin D derivative, respectively, such that eachformulation and API is sufficiently chemically and physically stable forpharmaceutical use.

Other foamable compositions are described in: U.S. Publication No.05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDALIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT ANDFOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596,published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30,2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.Publication No. 07-0020304, published on Jan. 25, 2007, entitledNON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMINGFOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732,547, filedon Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLECOMPOSITIONS AND KIT AND USES THEREOF; U.S. patent application Ser. No.11/732,547, filed on Apr. 4, 2007, KERATOLYTIC ANTIFUNGAL FOAM; U.S.patent application Ser. No. 11/767,442, filed on Jun. 22, 2007, entitledFOAMABLE COMPOSITIONS AND KITS COMPRISING ONE OR MORE OF A CHANNELAGENT, A CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, AND RELATED AGENTS ANDTHEIR USES; U.S. patent application Ser. No. 11/825,406, filed on Jul.5, 2007, entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICALCOMPOSITIONS THEREOF; U.S. patent application Ser. No. 11/900,072, filedon Sep. 10, 2006, entitled FOAMABLE VEHICLE AND VITAMIN AND FLAVONOIDPHARMACEUTICAL COMPOSITIONS THEREOF; and U.S. patent application Ser.No. 11/947,751, filed Nov. 29, 2007, entitled COMPOSITIONS WITHMODULATING AGENTS, all of which are incorporated herein by reference intheir entirety. More particularly any of the active ingredients; thesolvents; the surfactants; foam adjuvants; polymeric agents, penetrationenhancers; preservatives, humectants; moisturizers; and other excipientsas well as the propellants and methods listed therein can be appliedherein and are incorporated by reference.

A “stable foam” is defined herein as a composition, which upon releasefrom an aerosol can, creates a foam mass, which is sustained on asurface for at least one minute, more preferably at least two minutes,and yet more preferably for at least 5 minutes. A period of minutes isregarded as a short term, but nevertheless it allows a good and morethan sufficient period of time for a subject to receive foam dispensedon a body surface and to spread it or to transfer it to another regionand to spread it.

In terms of spreadability and absorption an acceptable foam is one, thatdoes not readily collapse upon dispensing on the skin; spreads easily ona skin surface; at least partially absorbed following rubbing onto theskin, and more preferably, substantially absorbed following rubbing onthe skin.

In terms of tactile properties, an acceptable foam is one, that: createsa pleasant feeling after application; leaves minimal oily residue; andleaves minimal shiny residual look.

Skin drying and skin barrier function. Short chain alcohols are known todry the skin and impair the integrity of the skin barrier. By contrast,including a film forming agent in the composition of the presentinvention Does not cause unwanted skin barrier damage.

Irritability. Due to the lack of lower alcohols (C1-C5) and improvementin skin barrier function, skin irritability is eliminated.

The petrolatum foam described herein has several advantages, whencompared with hydroalcoholic foam compositions.

-   -   (1) Breakability. The foam is thermally stable or substantially        so. Unlike hydroalcoholic foam compositions of the prior art,        the foam is not “quick breaking”, i.e., it does not readily        collapse upon exposure to body temperature environment.        Sheer-force breakability of the foam is clearly advantageous        over thermally induced breakability, since it allows comfortable        application and well directed administration to the target area;    -   (2) Skin drying and skin barrier function. Polar solvents and or        potent solvents can dry the skin and impair the integrity of the        skin barrier. By contrast, combining a polar solvent and or        potent solvent with an petrolatum emollient and or a hydrophobic        carrier, unwanted skin barrier damage is reduced; and    -   (3) Irritability. Due to the improvement in skin barrier        function, or further through addition of a humectant or a        moisturizer skin irritability is corrected or ameliorated.

In terms of usability, the foamable composition is most advantageous, asrevealed by clinical trials:

(i) Ease of application.

-   -   When foam is released it expands and allows easy spreading on        the target area. This advantage is particularly meaningful in        regards to the treatment of large skin surfaces.    -   Upon application, the foam readily spreads and absorbs into the        skin.

(ii) The Foam is Drip-Free

-   -   The foam is not liquid and therefore does not leak when applied.    -   This allows precise application, without the product being        spread on clothes or other parts of the body.

For the purpose of the specification the external limits of the variousranges given are approximate as will be appreciated by those skilled inthe art. Therefore, for the purpose of interpreting the outer limits ofthe range the limits shall be deemed to include up to a 20% leewayoutside the range, and preferably about at least al 0% leeway.

Fields of Applications

According to one or more embodiments, the foamable carrier and thefoamable pharmaceutical or cosmetic composition are intended foradministration to an animal or a human subject. In one or moreembodiments, the composition is intended to treat the skin, a bodysurface, a body cavity, a deep body cavity, or a mucosal surface, e.g.,the mucosa of the nose, mouth, eye, ear, respiratory system, vagina,rectum or colon.

By including an appropriate active agent in the compositions, thecomposition are useful in treating a patient having any one of a varietyof dermatological disorders, which include inflammation as one or theiretiological factors (also termed “dermatoses”), such as classified in anon-limiting exemplary manner according to the following groups:

Dermatitis including contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, chronic dermatitis of the hands andfeet, generalized exfoliative dermatitis, stasis dermatitis; lichensimplex chronicus; diaper rash;Bacterial infections including cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, staphylococcal scalded skin syndrome, folliculitis,furuncles, hidradenitis suppurativa, carbuncles, paronychial infections,and erythrasma;Fungal Infections including dermatophyte infections, yeast Infections;parasitic Infections including scabies, pediculosis, creeping eruption;

Viral Infections;

Disorders of hair follicles and sebaceous glands including acne,rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia,including male pattern baldness, alopecia greata, alopecia universalisand alopecia totalis; pseudofolliculitis barbae, keratinous cyst;Scaling papular diseases including psoriasis, pityriasis rosea, lichenplanus, pityriasis rubra pilaris;Benign tumors including moles, dysplastic nevi, skin tags, lipomas,angiomas, pyogenic granuloma, seborrheic keratoses, dermatofibroma,keratoacanthoma, keloid;Malignant tumors including basal cell carcinoma, squamous cellcarcinoma, malignant melanoma, paget's disease of the nipples, kaposi'ssarcoma;Reactions to sunlight, including sunburn, chronic effects of sunlight,photosensitivity;Bullous diseases including pemphigus, bullous pemphigoid, dermatitisherpetiformis, linear immunoglobulin A disease;Pigmentation disorders including hypopigmentation such as vitiligo,albinism and postinflammatory hypopigmentation and hyperpigmentationsuch as melasma (chloasma), drug-induced hyperpigmentation,postinflammatory hyperpigmentation;Disorders of cornification including ichthyosis, keratosis pilaris,calluses and corns, actinic keratosis;Pressure sores, open wounds, chronic wounds, open ulcers and burns;Disorders of sweating; andInflammatory reactions including drug eruptions, toxic epidermalnecrolysis, erythema multiforme, erythema nodosum, and granulomaannulare.

The same advantage is expected when the composition is topically appliedto a body cavity or mucosal surfaces, including, but not limited to thecranial cavity, the thoratic cavity, the abdominal cavity, the venteralcavity, the vagina, the rectum and penile cavities, the urinary tract,the nasal cavity, the mouth, the eye, the ear the peritoneum, the largeand small bowel, the caecum, bladder, and stomach, the cavity betweenthe uterus and the fallopian tubes, the ovaries and other body areas,which may accept topically-applied products. The composition is suitableto treat conditions of a body cavity and a mucosal membrane, such aspost-surgical adhesions, chlamydia infection, gonorrhea infection,hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genitalwarts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum.

According to one or more embodiments, the compositions are also usefulin the therapy of non-dermatological disorders by providing transdermalor trans-mucosal delivery of an active agent that is effective againstnon-dermatological disorders.

In one or more embodiments, the disorder is a health abnormality thatresponds to treatment with a hormone. A typical example of suchabnormality is sexual dysfunction in men and women whereby androgentherapy is successfully used to restore sexual function. Othernon-limiting examples of disorders/medical indications that are in thescope of treatment with a hormone according to the present invention areandrogen deficiency, estrogen deficiency, growth disorders,hypogonadism, cancer, vasomotor symptoms, menopausal disorders, vulvarand vaginal atrophy, urethritis, hypoestrogenism, osteoarthritis,osteoporosis, uterine bleeding, Hirsutism, Virilization, ovarian tumors,hypothalamic pituitary unit diseases, testicular tumors, prostatecancer, hypopituitarism, Klinefelter's syndrome, testicularfeminisation, orchitectomy, vasomotor symptoms (such as “hot flashes”)associated with the menopause, metabolic abnormalities and mooddisturbances.

Methodology

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein by reference.

Waterless Foam

-   -   1. Dissolve the polymers in the main solvent with heating or        cooling as appropriate for specific polymer. Add the all other        ingredients and heat to 75° C. to melt and dissolve the various        ingredients.    -   2. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   3. Cool to room temperature.        Note ASOS is preferably added at stage 2

Oily Waterless Foam

-   -   1. Mix all ingredients excluding polymers and heat to 75° C. to        melt and dissolve and obtain homogeneous mixture.    -   2. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   3. Cool to room temperature.

Emulsion Foam, Method (a)

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers in water with heating or cooling as appropriate        for specific polymer.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly internal phase to external phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. Cool to room temperature.

Emulsion Foam, Method (b)

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers in water with heating or cooling as appropriate        for specific polymer.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly external phase to internal phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6 Cool to room temperature.        Oily Foam with Phospholipids and/or Water    -   1. Swell the phospholipids in the main oily solvent under mixing        for at least 20 minutes until uniform suspension is obtained.    -   2. Add all other ingredients excluding polymers and heat to        75° C. to melt and dissolve and obtain homogeneous mixture.    -   3. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   4. Cool to room temperature.    -   5. In case of polymers dissolved in water or organic solvent,        dissolve the polymers in the solvent with heating or cooling as        appropriate for specific polymer and add to the oily mixture        under vigorous mixing at ˜40° C.

Petrolatum Zinc Oxide (Water/Oil) Emulsion

Step 1: Preparation of Water Phase

The water is heated to 70° C.

Step 2: Preparation of Oil Phase

The Oil Phase is prepared by mixing together of all ingredients and heatup to 70° C. Continue mixing until full melting for solid ingredients.

Step 3: PFF Formation

Step 3-a: Emulsification

The Water phase at 70-75° C. is added to the Oil phase in small portionsat 70° C. The emulsification is performed in presence of vigorousagitation continues until PFF uniformity is reached for at least 20 min.

Step 4: Addition of Zinc Oxide

Stop heating the PFF and slow addition of Zinc Oxide at 40-50° C. duringvigorous mixing. Continue mixing for at lease 30 min.

Petrolatum API (Water/Oil) Emulsion

The procedure is as above with API replacing or in addition to the Zincoxide. For sensitive ingredients cool to below 40° C. and add them withmild mixing.

Petrolatum Zinc Oxide (Solvent/Oil) Emulsion

The procedure is as above for water in petrolatum emulsion, but, DMI, orPG, or PEG 400 replaces the water.

Petrolatum API (Solvent/Oil) Emulsion

The procedure is as above with API replacing or in addition to the Zincoxide. For sensitive ingredients cool to below 40° C. and add them withmild mixing.

Petrolatum Zinc Oxide (Waterless)

Step 1: Preparation of Oil Phase

-   -   The Oil Phase is prepared by mixing together of all ingredients        and heat up to 65° C. Continue mixing until full melting for        solid ingredients.

Step 2: Addition of Zinc Oxide

-   -   Stop heating the oil phase and slow addition of Zinc Oxide at        40-50° C. during vigorous mixing. Continue mixing for at lease        30 min.

Production Under Vacuum

Optionally, the foamable formulation may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adessicator to remove oxygen prior to filing and crimping.

Loading and Testing of Canisters

-   -   An aerosol canister is filled with PFF and crimped with valve        using vacuum crimping machine.    -   Pressurizing is then carried out using a gas mixture comprising        n-Butane. Canisters are thereafter filled and preferably warmed        for 30 seconds in a warm bath at 50° C. and well shaken        immediately thereafter.    -   Each pressurized canister is subjected to bubble and crimping        integrity testing by immersing the canister in a 60° C. water        bath for 2 minutes. Canisters are observed for leakage as        determined by the generation of bubbles. Canisters releasing        bubbles are rejected.

Tests

By way of non limiting example the objectives of hardness, collapse timetests and aging are briefly set out below as would be appreciated by aperson of the art.

Hardness

LFRA100 instrument is used to characterize hardness. A probe is insertedinto the test material. The resistance of the material to compression ismeasured by a calibrated load cell and reported in units of grams on thetexture analyzer instrument display. Preferably at least three repeattests are conducted. The textural characteristics of a dispensed foamcan effect the degree of dermal penetration, efficacy, spreadability andacceptability to the user. The results can also be looked at as anindicator of softness. Note: the foam sample is dispensed into analuminum sample holder and filled to the top of the holder.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 minute.Thus foams which are structurally stable on the skin for at least oneminute are termed “short term stable” compositions or foams.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude.

FTC

FTC (Freeze Thaw Cycles) To check the foam appearance under extremeconditions of repeated cycles of cooling, heating, (first cycle)cooling, heating (second cycle) etc., commencing with −10° C. (24 hours)followed by +40° C. (24 hours) measuring the appearance and againrepeating the cycle for up to three times.

Chemical Stability

The amount of active agent present is analyzed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at 5° C., at 25° C., at, 40° C. and sometimes at 50° C. Atappropriate time intervals canisters are removed and the amount ofactive agent in the foam sample is measured.

Focus Group

Five healthy volunteers selected at random were give a sample of foamformulation and applied it to the skin on their forearm and were askedto complete a questionnaire.

Corneometer

Skin hydration is measured using a Corneometer® CM 825 instrument.(Courage+Khazaka, Koln, Germany). The measuring principle of theCorneometer® CM 825 is based on capacitance measurement of dielectricmedium. Any change in the dielectric constant due to skin surfacehydration alters the capacitance of a measuring capacitor. It can detecteven slight changes in the skin hydration level.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40X Camera(resolution 10MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

“Shakability” represents the degree to which the user is able tofeel/hear the presence of the liquid contents when the filledpressurized canister is shaken. Shaking is with normal mild forcewithout vigorous shaking or excessive force. When the user cannot sensethe motion of the contents during shaking the product may be consideredto be non shakable. This property may be of particular importance incases where shaking is required for affecting proper dispersion of thecontents.

Shakability scoring: Good shakability (conforms to required qualityspecification) 2 Moderate shakability (conforms to required qualityspecification) 1 Not shakable (fails to meet required qualityspecification) but may 0 still be flowable and allow foam formation ofquality Is substantially not able to pass through valve Block

Aging by Centrifugation:

1. Principle of Test

-   The centrifugation used in this procedure serves as a stress    condition simulating the aging of the liquid formulation under    investigation. Under these conditions, the centrifugal force applied    facilitates coalescence of dispersed globules or sedimentation of    dispersed solids, resulting in loss of the desired properties of the    formulation.

2. Procedure

-   -   2.1. Following preparation of the experimental formulation/s,        allow to stand at room temperature for >24 h.    -   2.2. Handle pentane in the chemical hood. Add to each        experimental formulation in a 20-mL glass vial a quantity of        pentane equivalent to the specified quantity of propellant for        that formulation, mix and allow formulation to stand for at        least 1 h and not more than 24 h.    -   2.3. Transfer each mixture to 1.5 mL microtubes. Tap each        microtube on the table surface to remove entrapped air bubbles.    -   2.4. Place visually balanced microtubes in the centrifuge rotor        and operate the centrifuge at 1,000 rpm for 10 min. The        centrifuge can be a BHG HEMLE Z 231 M.    -   2.5. Centrifugation can also be executed at a higher rpm for a        shorter period or a lower rpm for a longer period bearing in        mind the G force experienced by the formulations is many fold        greater than the one G to which a formulation would be exposed        to during its shelf life.

Stock Compositions

Non-limiting examples of how stock solutions are made up with andwithout API. Other stock solutions may be made using the samemethodology by simply varying adding or omitting ingredients as would beappreciated by one of the ordinary skills in the art.

The following examples further exemplify the stable non-alcoholicfoamable pharmaceutical carrier, pharmaceutical compositions thereof,methods for preparing the same, and therapeutic uses of thecompositions. The invention is described with reference to the followingexamples. For the purpose of the Examples below it was sufficient toapply a vacuum only at the crimping stage although for long termstability preferably any vacuum should be applied during manufacture aswell at a sufficient pressure so that any oxygen remaining in theformulation is virtually negligible. The examples are for the purposesof illustration only and are not intended to be limiting. Manyvariations may be carried out by one of ordinary skill in the art andare contemplated within the full scope the description herein.

EXAMPLES Section A—Non-Aqueous Formulations with at Least about 60% toabout 91% Petrolatum But without Oil and without Silicone Example A1 Two77% Petrolatum Waterless Foams with Zinc Oxide

5 6 Ingredient w/w % w/w % Petrolatum (Sofmetic ™ LMP) 50.00 50.00Petrolatum white (Pionier ® 5464) 27.00 27.00 Glyceryl monostearate 2.501.50 Sorbitan laurate 3.00 — Myristyl alcohol — 2.00 Stearyl alcohol2.50 2.50 Polysorbate 20 — 2.00 Zinc Oxide 15.00 15.00 Total product:100.00 100.00 Propellant: n-butane 20.00 20.00 Results Shakability yesyes Foam quality Good Excellent Color White White Odor No odor No odorFilm Good Good Density (g/mL) NM* 0.470 Viscosity (cP) 266,143 353,724*NM - Not Measured

-   Comments: The formulations of example 2 are waterless ointment foam,    without polymers, main hydrophobic petrolatum types are the    Sofinetic™ LMP which is characterized in the lowest range of melting    point for petroleum jelly USP and Petrolatum white. The ratio of    Sofinetic™ and Petrolatum white is balanced to obtain excellent foam    yet shakable non washable and heavy occlusive skin cover and greasy    skin feeling.

Example A2 90% Petrolatum Based Waterless Foam with Different API's

2a. Stock Waterless

Stock Waterless Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 58.82Petrolatum white (Pionier 5464) 31.76 Glyceryl monostearate 1.76 Stearylalcohol 2.94 Myristyl alcohol 2.35 Polysorbate 20 2.35 Total product:100.00 Propellant: n-butane 20.00 Results Shakability Yes Foam qualityGood Color Transparent-white Odor No odor Hardness (g) 87.88 CollapseTime (sec) >300 Viscosity (cP) 118,174 Centrifugation 3000 rpm StableWashable No

-   Comments: This formula was prepared in a pressurized glass bottle    and a translucent single phase was observed with the propellant    being dissolved in the petrolatum. See FIG. 3. The formula produced    good quality foam.    2b. Stock Waterless+API's

12 13 14 15 Ingredient w/w % w/w % w/w % w/w % Stock PFF 99.00 99.0098.00 99.00 Clotrimazole 1.00 Diclofenace sodium 1.00 Lidocaine base2.00 Terbinafine HCl 1.00 Total product: 100.00 100.00 100.00 100.00Propellant: n-butane 20.00 20.00 20.00 20.00 Results Shakability Yes yesyes yes Foam quality Good Good Good Good2c. Stock Waterless+API's

16 17 18 Ingredient w/w % w/w % w/w % Stock PFF 99.88 95.00 85.00Betamethasone 17 valerate 0.12 micronized Acyclovir 5.00 Azelaic acid15.00 Total product: 100.00 100.00 100.00 Propellant: n-butane 20.0020.00 20.00 Results Shakability yes yes yes Foam quality Good Good+Good+

Example A3 77% Petrolatum Based Waterless Foam with 15% w/w Zinc Oxidewith and without Additional API's

3a. Stock Waterless with Zinc Oxide

Stock Waterless Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 50.00Petrolatum white (Pionier 5464) 27.00 Glyceryl monostearate 1.50 Stearylalcohol 2.50 Myristyl alcohol 2.00 Polysorbate 20 2.00 Zinc Oxide 15.00Total product: 100.00 Propellant: n-butane 20.00 Results Shakability YesFoam quality Good Color White Odor No odor Hardness (g) 42.74 CollapseTime (sec) 130 Viscosity (Cp) 353,724 Centrifugation 3000 rpm StableWashable No3b. Stock Waterless with Zinc Oxide+API's

29 30 31 32 Ingredient w/w % w/w % w/w % w/w % Stock PFF 99.00 99.0099.00 98.00 Clindamicin phosphate 1.00 Clotrimazole 1.00 Diclofenacesodium 1.00 Lidocaine base 2.00 Total product: 100.00 100.00 100.00100.00 Propellant: n-butane 20.00 20.00 20.00 20.00 Results Shakabilityyes yes yes Yes Foam quality Good Good Good Good3c. Stock Waterless with Zinc Oxide+API's

33 34 35 36 Ingredient w/w % w/w % w/w % w/w % Stock PFF 99.00 95.0085.00 95.00 Terbinafine HCl 1.00 Acyclovir 5.00 Azelaic acid 15.00Caffeine 5.00 Total product: 100.00 100.00 100.00 100.00 Propellant:n-butane 20.00 20.00 20.00 20.00 Results Shakability yes yes yes YesFoam quality Good Good Good Good

Example A4 (Theoretical) 71% Petrolatum Based Waterless Foam with 15%w/w Zinc Oxide and ASOS

37 Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 45.00 Petrolatum white(Pionier 5464) 27.00 Glyceryl monostearate 1.50 Stearyl alcohol 2.50Myristyl alcohol 2.00 Polysorbate 20 2.00 Aluminum Starch OctenylSuccinate 5.00 Zinc Oxide 15.00 Total product: 100.00 Propellant:n-butane 20.00

Example A5 (Theoretical) 71% Petrolatum Based Waterless Foam with 15%w/w Zinc Oxide and Alkyl Lactate

38a 38b 38c Ingredient w/w % w/w % w/w % Petrolatum (Sofmetic ™ LMP)45.00 45.00 45.00 Petrolatum white (Pionier 27.00 27.00 27.00 5464)Glyceryl monostearate 1.50 1.50 1.50 Stearyl alcohol 2.50 2.50 2.50Myristyl alcohol 2.00 2.00 2.00 Polysorbate 20 2.00 2.00 2.00 AlkylLactate 5.00 5.00 5.00 Zinc Oxide 15.00 15.00 15.00 Total product:100.00 100.00 100.00 Propellant: n-butane 20.00 Propellant:: n-butaneand 20 iso-butane mixture Propellant: a PIB mixture 20 (Propane, iso-butanee and n- butanee)

Example A6 Unique 70% Petrolatum Based Non-Aqueous Foam with DMI andZinc Oxide

39 Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 20.00 Petrolatum white(Pionier 5464) 50.00 Steareth 2 0.75 Steareth 21 1.00 Glycerylmonostearate 0.50 Dimethyl Isosorbide 12.75 Zinc Oxide 15.00 Totalproduct: 100.00 Propellant: n-butane 20.00 Results Shakability Yes Foamquality Good Color White Odor No odor Washable No

Example A7 Unique 70% Petrolatum Based Non-Aqueous Foam with PEG 400 andZinc Oxide

40 Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 20.00 Petrolatum white(Pionier 5464) 50.00 Steareth 2 0.75 Steareth 21 1.00 Glycerylmonostearate 0.50 PEG 400 12.75 Zinc Oxide 15.00 Total product: 100.00Propellant:n-butane 20.00 Results Shakability Yes Foam quality Good+Color White Odor No Odor Washable No

Example A8 Unique 70% Petrolatum Based Non-Aqueous Foam with PropyleneGlycol and Zinc Oxide

41 Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 20.00 Petrolatum white(Pionier 5464) 50.00 Steareth 2 0.75 Steareth 21 1.00 Glycerylmonostearate 0.50 Propylene Glycol 12.75 Zinc Oxide 15.00 Total product:100.00 Propellant: n-butane 20.00 Results Shakability Yes Foam qualityGood Color White Odor No odor Washable No

Examples 9, 10 and 11 are waterless emulsions of liquid hydrophilicsolvents DMI, PEG 400 or Propylene glycol, stabilized in petrolatumbase. It has been unexpectedly observed that replacing the water inabove water in petrolatum emulsions, yielded high quality foams.

Example A9 Formulations with Petrolatum Combinations

PART A- Minimal Ingredients of 60% petrolatum a foam adjuvant a polymerand API 42 Ingredients w/w % Petrolatum (Sofmetic ™ 33 LMP) Petrolatumwhite 27 (Pionier ® 5464) Oleyl alcohol 10 Aluminum Starch 15 OctenylSuccinate Zinc Oxide 15 Total product: 100 Propellant: n-butane 20Results Viscosity (cP) 249866.7 Viscosity (0.1 RPM cP) 175642.5Shakability 2 Foam quality Good Color White Odor No odor Density (g/mL)0.533 collapse >300/G

PART B - 72% Petrolatum, an oil, a surfactant, a foam adjuvant, apolymer and API with different propellants 43A 43B 43C Ingredient w/w %w/w % w/w % Petrolatum (Sofmetic ™ 45 45 45 LMP) Petrolatum white(Pionier ® 27 27 27 5464) IPM 4 4 4 Myristyl alcohol 2 2 2 AluminumStarch Octenyl 5 5 5 Succinate Polysorbate 20 2 2 2 Zinc Oxide 15 15 15Total product: 100 100 100 Propellant: n-butane 20 Propellant:: n-butaneand 20 iso-butane mixture Propellant: a PIB mixture 20 (Propane,iso-butanee and n-butanee) Results Viscosity (cP) 210195.1 Viscosity(0.1 RPM cP) 148608.3 Shakability 2 2 2 Foam quality G G G Color Whitewhite white Odor no odor no odor no odor Film Density (g/mL) 0.393 0.5010.5 collapse NR >300/G >300/G hardness 34.08 >100 g >100 g

PART C - 61% to 81% Petrolatum Formulations with and without alkyllactate and DMI with API. Formulation 47 is with different propellants.44 45 46 47a 47b 47c 48 Ingredient w/w % w/w % w/w % w/w % w/w % w/w %w/w % Petrolatum 64 35 60 45 45 45 50 (Sofmetic ™ LMP) Petrolatum 27 2727 27 27 27 27 white (Pionier ® 5464) Glyceryl 1.5 1.5 1.5 1.5 1.5 1.51.5 monostearate Stearyl alcohol 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Myristylalcohol 2 2 2 2 2 2 2 DMI 5 Polysorbate 20 2 2 2 2 2 2 2 Alkyl Lactate 55 5 Zinc Oxide 1 30 5 15 15 15 10 Total product: 100 100 100 100 100 100100 Propellant: n- 20 20 20 20 20 butane Propellant:: n- 20 butane andiso- butane mixture Propellant: a 20 PIB mixture (Propane, iso- butaneand n- butane) Results Viscosity (cP) NR 212114.7 231310.6 Viscosity(0.1 RPM 326330.4 1488215.7 638903.6 118694.7 163005.2 cP) (0.3 RPM)(0.3 RPM) (0.3 RPM) Shakability 1 2 1 2 1 1 2 Foam quality G G G F G G GColor white White white white white white white Odor v.f.o. no odor noodor no odor no odor no odor no odor Density (g/mL) 0.423 0.497 0.443 NR0.478 0.497 0.402 collapse NR NR NR NR >300/G >300/G NR hardness 35.5740.64 41.75 NR 93.33 NR 31.04

PART D- 71% to 77% Petrolatum Formulations with and without alkyllactate and DMI with API. Formulation 49 is with different propellants.48 49 A 49 B 49 C Ingredient w/w % w/w % w/w % w/w % Petrolatum 50 45 4545 (Sofmetic ™ LMP) Petrolatum white 27 27 27 27 (Pionier ® 5464)Glyceryl 1.5 1.5 1.5 1.5 monostearate Stearyl alcohol 2.5 Myristylalcohol 2 2 2 2 DMI 5 Polysorbate 20 2 Alkyl Lactate 5 5 5 Zinc Oxide 1015 15 15 Total product: 100 100 100 100 Propellant: n- 20 20 butanePropellant:: n- 20 butane and iso- butane mixture Propellant: a PIB 20mixture (Propane, iso-butane and n- butane) Results Viscosity (cP)231310.6 301695.6 Viscosity (0.1 RPM 163005.2 171003.5 cP) Shakability 22 1 1 Foam quality G FG G G Color white White white white Odor no odorno odor no odor no odor Film Density (g/mL) 0.402 NR 0.452 0.473collapse NR NR >300/G >300/G hardness 31.04 NR 65.41 >100 g

PART E - Focus Group Focus Group (4) Formulation 45 46 48 49 STICKY 1113 12 9 ODOR 11 8 13 16 SHINY 11 13 12 9 SATISFACTION 13 14 15 10 FILM14 7 10 18 Total 60 51 62 62

Comments: Each individual applied the foam to their skin and completed aquestionnaire when they gave a mark for each foam trait between 1 and 5for each trait where 5 is excellent and 1 is poor. A preferredformulation is one with an average score eg about 60 or more.

PART F—A Study of Skin-Hydration Effect of Petrolatum Vehicle of ExampleA9

The study is single blind (study recipient is blinded). Healthy subjectsare applied with single dose of formulations as shown in Example A9.Skin hydration is measured using a Corneometer® CM 825 instrument.(Courage+Khazaka, Koln, Germany). The measuring principle of theCorneometer® CM 825 is based on capacitance measurement of dielectricmedium. Any change in the dielectric constant due to skin surfacehydration alters the capacitance of a measuring capacitor. It can detecteven slight changes in the skin hydration level.

Skin hydration level is assessed at baseline with the Corneometer® CM825. The formulations (about 0.075 g) is applied. Corneometers testedskin hydration after 15 mins following application. The skin was thenwashed and the hydration again measured.

Four circles of the same size are drawn on the forearms (applying area),two on each side and will be numbered from 1 to 4: The measurements weretaken from marked areas only, since those the areas that were exposed totreatment.

Corneometer Results Formulation 45 46 48 49A ZT (Zero 37.5 40.75 34 39Time) av (4) BEFORE 39.25 32 36.5 30.25 WASHING AFTER 57.25 64 56.560.75 WASHING

Comments: After washing a protective layer was still felt on he skin butthe corneometer was able to detect about a 50% improvement in skinhydration as a result of the presence of the occlusive Zinc Oxideformulations even after a short period of 15 mins suggesting utility forexample for nappy use.

Example 12 Exemplary Prophetic Foamable Formulations

Exemplary concentrations of active agents in foamable compositions areset out in Table 2. Each active agent is added into, for example, any ofthe carriers listed in any of the above Examples in a therapeuticallyeffective concentration and amount. The methodology of addition is wellknown to those of the art. The composition is adjusted in each case sothat it is made up to 100% w/w as appropriate by solvent or petrolatum.

TABLE 2 Exemplary Concentrations of Examples of Active Agents ClassConcentration Exemplary Use Hydrocortisone 1% Steroid responsiveinflammation and acetate Betamethasone 0.12%   psoriasis or atopicdermatitis valerate Clobetasol 0.05%   proprionate Acyclovir 5% Viralinfection, herpes Ciclopirox 1% Fungal infection, seborrhea, dandruff,Clindamycin 1-2% Bacterial infection, acne, rosacea, Azelaic acid 15% Acne, rosacea, pigmentation disorder and various dermatoses Metronidazol0.25%-2%   Rosacea, bacterial infections and parasite infestationsDiclofenac 1% Osteoarthritus, joint pain Tacrolimus 0.2%   Atopicdermatitis, eczema and inflammation Caffeine 5% anti-celluliteClotrimazole 1% Fungal infection Lidocaine base 2% Local anaestheticTerbinafine HCL 1% Fungal infection Gentamycin 0.1%   Bacterial skininfections, burns or ulcers Dexpanthenol 5% Wounds, ulcers, minor skininfections Urea  5-10% Emollient and keratolytic Atopic dermatitis,eczema, ichthyosis and hyperkeratotic skin disorders Ammonium  12%-17.5% Dry scaly conditions of the skin lactate includingichthyosis Povidone-iodine 10%  Antimicrobial - antiseptic Calcitriol~0.005%    Psoriasis Calcipotriol ~0.005%    Psoriasis

Note, all the above active agents have a degree of solubility in wateror petrolatum or the composition other than clobestol proprionate, whichis practically insoluble; tacrolimus, which is insoluble in water; andbetamethasone valerate which although has very limited solubility isnevertheless, surprisingly soluble at least to a degree in thecompositions, in the water phase. Note, for example, calcipotriolsolubility in water is 0.6 μg/mL.

The above examples represent different drug classes and it is to beunderstood that other drugs belonging to each of the classes representedabove or described elsewhere in the specification may be included andused in the compositions in a safe and effective amount.

Section B—Formulations with in Excess of 50% Petrolatum and Oil, withoutSilicone and with No Water.

Example B1 High Content Petrolatum Based Non-Aqueous Foam with MineralOil and PPG

011 011A Ingredient w/w % w/w % Petrolatum (Sofmetic ™ LMP) 75.00 77.32Light Mineral Oil 3.00 3.09 PPG stearyl ether 5.00 5.15 Behenyl alcohol[HLB 1.9] 1.00 1.03 Cetostearyl alcohol 3.00 3.09 ceteth 20 [HLB 15.7]3.00 3.09 Glyceride Monostearate 1.00 1.03 (GMS) Span ® 80 [HLB 4.3]4.00 4.12 Tween ® 20 [HLB 16.7] 2.00 2.06 Aluminum starch octenyl 3.00 —succinate (ASOS) Total product: 100.00 100.00 Propellant: [propane: iso-11.50 11.50 butane: n-butane] mixture Results Shakability yes yes Foamquality Good^(a) Good^(a) Color white white Odor No odor No odor Density0.172 NM Collapse Time >300 seconds NM ^(a)towards excellent

-   Comments: This formula (having an average HLB of 9.36) was prepared    in a pressurized glass bottle and a milky homogenous single phase    was observed with the propellant being dissolved in the petrolatum    (see FIGS. 2 a and 2 b below). After being subjected to about 10    minutes centrifugation at 1000 rpm, the formulation remained stable.    Comparing this foam to the foam prepared according to Example 1, it    can be seen that the presence of a large amount of liquid solvent    (e.g. PPG) in Example 1 appears to facilitate the reduction or    elimination of a liquid surfactant from the formulation when a waxy    or solid surfactant is present. ASOS contributed to an improved skin    feeling. The formulation produced a good quality foam in the absence    of ASOS.

Example B2 Effect of Surfactant on High Content Petrolatum BasedNon-Aqueous Foam with Mineral Oil and PPG

11-1 11-2 11-3 Ingredient w/w % w/w % w/w % Petrolatum (Sofmetic ™ LMP)75.00 75.00 75.00 Light Mineral oil 3.00 3.00 3.00 PPG stearyl ether5.00 5.00 5.00 Tween ® 20 [HLB 16.7] 14.00 7.00 Span ® 80 [HLB 4.3]14.00 7.00 Aluminum starch octenyl succinate 3.00 3.00 3.00 Totalproduct: 100.00 100.00 100.00 Propellant: propane: iso-butane: 10% 10%10% n-butane mixtures Average HLB 16.70 4.3 10.50 Results ShakabilityGood Good Good Foam quality Fairly Fairly Fairly Good Good^(b) GoodColor White White White Odor No No No odor odor odor ^(b)One sampleshowed an almost good foam.

-   Comments: In these experiments formulations containing liquid    surfactants of varying HLB values were prepared by modifying the    ratio between Tween 20, a liquid surfactant having an HLB of 16.7,    and Span 80, a liquid surfactant having an HLB of 4.3. No    significant changes were observed between the various formulations    and resulting foams. A different mixture of propellant was tried at    11.5%. Foam quality observed in all three cases was fairly good. In    addition, two formulations containing no surfactant (one with    aluminum starch octenyl succinate and the other without) were    prepared but were not able to produce anything like a viable or    usable foam.

Example B3 High 75% content Petrolatum Based Non-Aqueous Foam withMineral Oil and PPG with Active Ingredients

Ingredients w/w White Petrolatum (sofmetic) 75.00 light Mineral oil 3.00PPG 15 stearyl ether 4.93 Cetostearyl alcohol 3.00 Behenyl alcohol 1.00Ceteth 20 3.00 steareth 2 — Glyceryl mono stearate 1.00 Sorbitanmonooleate 80 4.00 polysorbate 20 2.00 Aluminum starch octenyl 3.00succinate Calcipotriol 0.005 Betamethasone Dipropionate 0.064 Total100.00 Propellant: propane; iso-butane; 11.5% n-butane mixtures ResultsShakability Good Appearance: Quality Good Odor No odor Color WhiteDensity 0.172 Collapse time at 36° C. (sec.) >300 Hardness 20.29

-   Comments: High and relatively Low petrolatum formulations appear to    be good waterless carriers for active ingredients. The hardness    results observed indicates that both the high and relatively low    petrolatum concentrations produce soft foams. The results with    active ingredients can be readily extrapolated to apply to the    carrier without any active ingredient since the amount of active    agent is well below 0.1% and therefore any effect on hardness is    anticipated to be negligible. The vitamin D derivative may easily be    replaced by an effective amount of another such as calcitriol.    Likewise the steroid may be replaced by an effective amount of    another steroid such as BMV. Although a combination of API's is    exemplified the formulation may alternatively contain only one of    them.

Example B4 High 79%-85% Petrolatum Based Non-Aqueous Foam with MineralOil PPG-15 Stearyl Ether and Cetostearyl Alcohol with Active IngredientsCalcipotriol and Betamethasone dipropionate (BMD)

Ingredients 026 027 028 029 030 White Petrolatum (sofmetic) 85.0 81.083.0 83.0 79.0 light Mineral oil 3.0 3.0 3.0 3.0 3.0 Cetostearyl alcohol3.0 3.0 3.0 3.0 3.0 Ceteth 20 3.0 3.0 3.0 3.0 3.0 Glyceryl monostearate1.0 1.0 1.0 1.0 1.0 Sorbitan monooleate — 4.0 — — 4.0 Polysorbate 20 — —2.0 — 2.0 Polysorbate 80 — — — 2.0 — Calcipotriol 0.005 0.005 0.0050.005 0.005 Betamethasone dipropionate 0.064 0.064 0.064 0.064 0.064PPG-15 stearyl ether 4.93 4.93 4.93 4.93 4.93 Propellant 8.00 8.00 8.008.00 8.00 (propane/butane/isobutene) Total: 100.0 100.0 100.0 100.0100.0 Results at time point zero: Shakability good moderate Good poormoderate Density [g/mL] 0.177 0.215 0.202 0.257 0.165 Foam Quality FG GG- G- G Foam Color White White White White White Foam Odor no odor noodor no odor no odor no odor Collapse Time (sec) — >300 — — — Assay ofCalcipotriol (% w/w) 0.0050 0.0048 0.0047 0.0047 0.0050 Assay ofBetamethasone 0.061 0.063 0.061 0.060 0.063 dipropionate (% w/w) Resultsafter 2 months at 40° C.: Shakability good good Good good good Density[g/mL] — 0.158 — — 0.152 Foam Quality FG G- FG FG G- Foam Coloroff-white White off-white off-white White Foam Odor faint odor faintodor faint odor faint odor faint odor Assay of Calcipotriol (% w/w)0.0036 0.0046 0.0024 0.0041 0.0044 Assay of Betamethasone 0.052 0.0600.038 0.055 0.059 dipropionate (% w/w) Results after 3 months at 40° C.:Shakability good good Good good good Density [g/mL] — — — — — FoamQuality FG G- FG FG G- Foam Color off-white White off-white off-whiteWhite Foam Odor faint odor faint odor faint odor faint odor faint odorAssay of Calcipotriol (% w/w) 0.0036 0.0046 0.0024 0.0041 0.0044 Assayof Betamethasone 0.052 0.060 0.038 0.055 0.059 dipropionate (% w/w)

-   Comments: The addition of sorbitan stearate or of polysorbate    surfactants enhanced the foam quality. The formulations without    sorbitan stearate were less stable physically and chemically.    Vehicles 27 and 30 displayed physical and chemical stability for    three months at 40 C. It is possible that the polysorbate surfactant    may effect stability. Although combined herein in one carrier the    active ingredients may in an alternative embodiment be presented in    two separate canisters in the same or different carriers adapted to    maximize the stability of the active ingredients. For example, the    steroid formulation may have a modulating agent present such that    the formulation is at an artificial acid pH. Likewise the vitamin D    derivative may have a modulating agent present such that the    formulation is at an artificial basic pH. The vitamin D derivative    may easily be replaced by an effective amount of another such as    calcitriol. Likewise the steroid may be replaced by an effective    amount of another steroid such as BMV. Although a combination of    API's is exemplified the formulation may alternatively contain only    one of them.

Example B5 High 85% Petrolatum Based Non-Aqueous Foam with Mineral OilPPG-15 Stearyl Ether and Lecithin with Active Steroid IngredientsBetamethasone Valerate (BMV); Betamethasone Dipropionate; ClobetasolPropionate; and Triamcinolone Acetonide A) Betamethasone Valerate

Ingredients White Petrolatum (sofmetic) 85 Light Mineral oil 3 PPGstearyl ether 8.48 Lecithin 1.4 Sorbitan stearate 2 Betamethasonevalerate 0.12 Total 100 Results at time point zero: Shakability GoodDensity [g/mL] 0.103 Foam Quality Good Foam Color White Foam Odor noodor Collapse Time (sec) >300 Assay of Betamethasone valerate 0.116 (%w/w) Results after 2 months at 40° C.: Shakability Good Density [g/mL]0.112 Foam Quality Good Foam Color White Foam Odor no odor Collapse Time(sec) 190 Assay of Betamethasone valerate 0.115 (% w/w) Results after 3months at 40° C.: Shakability Good Density [g/mL] 0.108 Foam QualityGood Foam Color White Foam Odor faint odor Collapse Time (sec) 130 Assayof Betamethasone valerate 0.109 (% w/w)

B) Betamethasone Dipropionate

Ingredients White Petrolatum (sofmetic) 85 Light Mineral oil 3 PPGstearyl ether 8.54 Lecithin 1.4 Sorbitan stearate 2 Betamethasonedipropionate 0.064 Total 100 Assay of Betamethasone dipropionate (% w/w)Time point zero 0.061 after 2 weeks at 40° C. 0.059

C) Clobetasol Propionate

Ingredients White Petrolatum (sofmetic) 85 Light Mineral oil 3 PPGstearyl ether 8.55 Lecithin 1.4 Sorbitan stearate 2 Clobetasolpropionate 0.05 Total 100 Assay of Clobetasol propionate (% w/w) Timepoint zero 0.049 after 2 weeks at 40° C. 0.047

D) Triamcinolone Acetonide

Ingredients White Petrolatum (sofmetic) 85 Light Mineral oil 3 PPGstearyl ether 8.54 Lecithin 1.4 Sorbitane stearate 2 Betamethasonedipropionate 0.1 Total 100 Assay of Triamcinolone Acetonide (% w/w) Timepoint zero 0.096 after 2 weeks at 40° C. 0.100

-   Comments: The lecicthin vehicle showed good foam quality and a    collapse time in excess of 300 secs and was found to be stable at 40    C for several months with BMV. Preliminary accelerated stability    tests for two weeks with other steroids indicated that the vehicle    can be stable with other steroids. It is predicted that if the    lecithin carrier were to be stability tested with an effective    amount of other steroids for example halobetasol propionate or    hydrocortisone butyrate, the formulations would also show stability.

Example B6 Petrolatum, mineral oil formulations with and withoutlecithin and PPG 15 Stearyl Ether

PART A wherein the petrolatum mineral oil combination is about at least75% and the petrolatum is in excess of 50%. 038 039 040 041 042Ingredient % w/w % w/w % w/w % w/w % w/w Zinc oxide 15 15 15 15 15Petrolatum 71 58.5 58.5 71 56 (sofmetic) Mineral oil, 5 20 20 5 20 lightLecithin 1 1 1 Ceteth 20 3 3 3 Sorbitan 3 3 stearate PPG 15 5 5 5stearyl ether GMS 0.5 0.5 Cetostearyl 3 3 alcohol Control 100 100 100100 100 Propellant 8 8 8 8 8 AP70

PART B wherein the petrolatum mineral oil combination is about at least65% and the petrolatum is in the majority. 043 044 045 046 047Ingredient % w/w % w/w % w/w % w/w % w/w Zinc oxide 15 15 15 15 15Petrolatum 46 46 56 61 61 (sofmetic) Mineral oil, 20 20 20 5 5 lightLecithin 1 1 1 1 1 Ceteth 20 3 3 Sorbitan 3 3 3 stearate PPG 15 15 15 515 15 stearyl ether GMS Cetostearyl alcohol Control 100 100 100 100 100Propellant 8 8 8 8 8 AP70

PART C wherein the petrolatum mineral oil combination is about at least78% and the petrolatum is in excess of 50%. 048 049 050 Ingredient % w/w% w/w % w/w Zinc oxide 15 15 15 Petrolatum 73.5 58.5 73.5 (sofmetic)Mineral oil, 5 20 5 light Lecithin Ceteth 20 3 Sorbitan 3 3 stearate PPG15 stearyl ether GMS 0.5 0.5 0.5 Cetostearyl 3 3 3 alcohol Control 100100 100 Propellant 8 8 8 AP70

PART C - Results at zero time, for FTC (4 cycles), and after two weeksat 40 C. FTC 40° C., 40° C., Test T-0 upr FTC inv upr inv 038 Quality 55 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2 Density(g/ml) 0.115 0.118 0.115 0.117 0.113 Collapse time(sec) >300/G >300/G >300/G >300/G >300/G 039 Quality 5 5 5 5 5 Color 1 11 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2 Density (g/ml) 0.165 0.1550.152 0.135 0.155 Collapse time (sec) >300/G >300/G >300/G >300/G >300/G040 Quality 5 5 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 22 Density (g/ml) 0.165 0.158 0.168 0.140 0.148 Collapse time(sec) >300/G 200/F >300/G >300/FG >300/G 041 Quality 5 5 5 5 5 Color 1 11 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2 Density (g/ml) 0.145 0.1400.123 0.120 0.120 Collapse time (sec) 180/F >300/F 140/F 190/F 130/F 042Quality 5 5 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2Density (g/ml) 0.155 0.140 0.128 0.145 0.140 Collapse time (sec) 220/F130/F 100/F 150/F 130/F 043 Quality 5 5 5 5- 5- Color 1 1 1 1 1 Odor 2 22 2 2 Shakability 2 2 2 2 2 Density (g/ml) 0.148 0.147 0.132 0.128 0.117Collapse time (sec) >300/F 70/F 70/F 80/F 80/F 044 Quality 5 5 5 5 5Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2 Density (g/ml)0.150 0.127 0.105 0.142 0.130 Collapse time (sec) >300/FG 280/FG 300/FG90/F 90/F 045 Quality 5 5 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2Shakability 2 2 2 2 2 Density (g/ml) 0.138 0.122 0.118 0.127 0.123Collapse time (sec) >300/G 60/FG 280/FG 120/F 80/F 046 Quality 5 5 5 5 5Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 2 2 2 2 Density (g/ml)0.160 0.158 0.162 0.133 0.128 Collapse time (sec) 180/F 120/F 140/F100/F 80/F 047 Quality 5 5 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2Shakability 2 2 2 2 2 Density (g/ml) 0.115 n/r 0.102 0.123 0.112Collapse time (sec) >300/FG block 270/F 300/FG 260/FG 048 Quality 5 5 55 5 Color 1 1 1 1 1 Odor 2 2 2 2 2 Shakability 2 1 1 2 2 Density (g/ml)0.200 n/r 0.145 0.148 0.148 Collapse time (sec) >300/G bolck >300/ 170/F110/F FG 049 Quality 5 5 5 5 5 Color 1 1 1 1 1 Odor 2 2 2 2 2Shakability 2 2 2 2 2 Density (g/ml) 0.190 0.160 0.162 n/r n/r Collapsetime (sec) >300/FG >300/G >300/G block block 050 Quality 5 5 5 5 5 Color1 1 1 1 1 Odor 2 2 2 2 2 Shakability 1 1 1 2 2 Density (g/ml) 0.2100.168 0.175 0.165 0.150 Collapse time (sec) >300/G block >300/G >300/G>300/G

-   Comments: Formulations 39 and 40 appeared to be the most stable. FTC    was four cycles.

Example B7 Exemplary (Prophetic) Foams Containing Pharmaceutical ActiveIngredients (API)

Exemplary concentrations of active ingredients in foamable compositionsare set out in Table 1. Each active ingredient is added into, forexample, any of the carriers listed in any of the above Examples in atherapeutically effective concentration and amount. The methodology ofaddition is well known to those of the art. The composition is adjustedin each case so that it is made up to 100% w/w by either a solvent orpetrolatum.

TABLE 1 Exemplary Concentration ranges of some APIs which are addable tofoams Class Concentration Exemplary Use Hydrocortisone acetate 1%Steroid responsive inflammation and psoriasis Betamethasone valerate0.12%   or atopic dermatitis Clobetasol proprionate 0.05%   Acyclovir 5%Viral infection, herpes Ciclopirox 1% Fungal infection, seborrhea,dandruff, Clindamycin 1-2%  Bacterial infection, acne, rosacea, Azelaicacid 15%  Acne, rosacea, pigmentation disorder and various dermatosesMetronidazol 0.25%-2%   Rosacea, bacterial infections and parasiteinfestations Diclofenac 1% Osteoarthritus, joint pain Tacrolimus 0.2%  Atopic dermatitis, eczema and inflammation Caffeine 5% anti-celluliteClotrimazole 1% Fungal infection Lidocaine base 2% Local anaestheticTerbinafine HCL 1% Fungal infection Gentamycin 0.1%   Bacterial skininfections, burns or ulcers Dexpanthenol 5% Wounds, ulcers, minor skininfections Urea  5-10% Emollient and keratolytic Atopic dermatitis,eczema, ichthyosis and hyperkeratotic skin disorders Ammonium lactate12%-17.5% Dry scaly conditions of the skin including ichthyosisPovidone-iodine 10%  Antimicrobial - antiseptic Calcipotriol ~0.005%   Psoriasis Calcitriol ~0.005%    Psoriasis

The above examples represent different drug classes and it is to beunderstood that other drugs belonging to each of the classes representedabove or described elsewhere in the specification may be included andmay be used in the compositions in a safe and effective amount.

Section C—Formulations with in Excess of 80% Combinations of Petrolatumand Oil, without Silicone and with No Water.

Example C1 30% Petrolatum and in excess of 50% Oil/PPG 15 Stearyl EtherBased Non-Aqueous Foam

005 005-A Ingredient w/w % w/w % Petrolatum (Sofmetic ™ LMP) 30.00 30.61Light Mineral Oil 39.00 39.80 PPG stearyl ether 15.00 15.31 Behenylalcohol [HLB 1.9] 1.00 1.02 Cetostearyl alcohol 4.00 4.08 ceteth 20 [HLB15.7] 4.00 4.08 Steareth 2 [HLB 4.7] 3.00 3.06 Glyceride Monostearate(GMS) 2.00 2.04 [HLB 3.4] Aluminum starch octenyl succinate (ASOS) 2.00— Total product: 100.00 100.00 Propellant: [propane: iso-butane:n-butane] 10.00 10.00 mixture Results Shakability Yes yes Foam qualityGood^(a) Good^(a) Color White white Odor No odor No odor Density 0.198NM Collapse Time >300 seconds NM ^(a)towards excellent; NM: not measured

-   Comments: This formula (having an average HLB of 8.56) was prepared    in a pressurized glass bottle and a milky homogenous single phase    was observed with the propellant being dissolved in the petrolatum    (see FIGS. 1 a and 1 b below). A foam of similar properties was    obtained for the same composition using an n-butane propellant (18%)    instead of [propane: iso-butane: n-butane] propellant mixture. ASOS    contributed to an improved skin feeling. The Formulation produced a    good quality foam in the absence of ASOS.

Example C2 30% Petrolatum and in Excess of 50% Oil/PPG 15 Stearyl EtherBased Non-Aqueous Foam with Active Ingredients

Ingredients w/w White Petrolatum (sofmetic) 30.00 light Mineral oil39.00 PPG 15 stearyl ether 14.93 Cetostearyl alcohol 4.00 Behenylalcohol 1.00 Ceteth 20 4.00 steareth 2 3.00 Glyceryl mono stearate 2.00Aluminum starch octenyl succinate 2.00 Calcipotriol 0.005 BetamethasoneDipropionate 0.064 Total 100.00 Propellant: propane; iso-butane; n- 10%butane mixtures Results Shakability Good Appearance: Quality Good OdorNo odor Color White Density 0.198 Collapse time at 36° C. (sec.) >300Hardness 19.44

-   Comments: The formulation appears to be a good waterless carrier for    active ingredients. The hardness results observed indicates that the    high oil petrolatum combination concentrations produce soft foams.    The results with active ingredients can be readily extrapolated to    apply to the carrier without any active ingredient since the amount    of active agent is well below 0.1% and therefore any effect on    hardness is anticipated to be negligible. The vitamin D derivative    may easily be replaced by an effective amount of another such as    calcitriol. Likewise the steroid may be replaced by an effective    amount of another steroid such as BMV. Although a combination of    API's is exemplified the formulation may alternatively contain only    one of them.    Section D—Formulations with in Excess of 50% Petrolatum without Oil,    without Silicone and with Up to about 26% Water.

Example D1 Two Petrolatum Water in Oil Emulsion Foams with Zinc Oxide

1a. Formulation Contain Polymer

1 2 w/w % w/w % Ingredient Petrolatum (Sofmetic ™ 55.00 70.00 LMP)Glyceryl monostearate 0.50 0.50 Sorbitan laurate 1.00 1.00 Cetyl alcohol1.00 1.00 Water, purified 26.25 11.30 Sodium Carboxymethyl 0.25 0.20cellulose Polysorbate 20 1.00 1.00 Zinc Oxide 15.00 15.00 Total product:100.00 100.00 Propellant: n-butane 20.00 20.00 Results Shakability yesyes Foam quality Good+ Good Color White White Odor No odor No odor FilmMedium Medium Density (g/mL) NM* NM* Viscosity (cP) NM* NM* *NM—NotMeasured1b. Formulation without Polymer

3 4 Ingredient w/w % w/w % Petrolatum (Sofmetic ™ LMP) — 20.00Petrolatum white (Pionier ® 5464) 70.00 50.00 steareth 2 — 0.75 steareth21 — 1.00 Glyceryl monostearate 0.50 0.50 Sorbitan laurate 1.00 —Stearyl alcohol 1.00 — Water, purified 11.50 12.75 Polysorbate 20 1.00 —Zinc Oxide 15.00 15.00 Total product: 100.00 100.00 Propellant: n-butane20.00 20.00 Results Shakability yes Yes Foam quality Good Good ColorWhite White Odor No odor No odor Film Excellent Medium Density (g/mL)NM* 0.560 Viscosity (cP) 390,0516 186,093 *NM—Not Measured

-   Comments: Example one, table 1a, shows formulations comprising    polymers whereas 1b polymer-less foams. It should be noted, that    good foams and desired properties are obtained with and without    polymers.

Example D2 Petrolatum Water in Oil Emulsion Foam with Different API's

2a. Stock Emulsion

Stock Emulsion Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 23.53Petrolatum white (Pionier ® 5464) 58.82 Steareth 2 0.88 Steareth 21 1.18Glyceryl monostearate 0.59 Water, purified 15.00 Total product: 100.00Propellant: n-butane 20.00 Results Shakability Yes Foam quality Good+Color White Odor No odor Hardness (g) 69.62 Collapse Time (sec) >300Viscosity (cP) 218,553 Centrifugation 3000 rpm Stable Washable No2b. Stock Emulsion+API's

7 8 9 Ingredient w/w % w/w % w/w % Stock PFF 99.00 99.00 99.00Clindamicin phosphate 1.00 Clotrimazole 1.00 Diclofenace sodium 1.00Total product: 100.00 100.00 100.00 n-butane 20.00 20.00 20.00 ResultsShakability yes yes Yes Foam quality Good+ Good+ Good+2c. Stock Emulsion+API's

10 11 Ingredient w/w % w/w % Stock PFF 99.88 95.00 Betamethasone 17valerate 0.12 micronized Caffeine 5.00 Total product: 100.00 100.00n-butane 20.00 20.00 Results Shakability yes Yes Foam quality Good+Good+

Example D3 Petrolatum Water in Oil Emulsion Foam with 15% w/w Zinc Oxidewith and without Additional API's

3a. Stock Emulsion with Zinc Oxide

Stock Emulsion Ingredient w/w % Petrolatum (Sofmetic ™ LMP) 20.00Petrolatum white (Pionier 5464) 50.00 Steareth 2 0.75 Steareth 21 1.00Glyceryl monostearate 0.50 Water, purified 12.75 Zinc Oxide 15.00 Totalproduct: 100.00 Propellant: n-butane 20.00 Results Shakability Yes Foamquality Good+ Color White Odor No odor Hardness (g) 79.60 Collapse Time(sec) >300 Viscosity (cP) 186,093 Centrifugation 3000 rpm StableWashable No

-   Zinc oxide is uniformly dispersed in the formula, no aggregation or    flocculation of zinc oxide was observed. The emulsion is non    washable and enable tick occlusive persistent layer on the applied    skin.    3b. Stock Emulsion with Zinc Oxide+API's

19 20 21 22 23 Ingredient w/w % w/w % w/w % w/w % w/w % Stock PFF 99.0099.00 99.00 98.00 99.00 Clindamicin phosphate 1.00 Clotrimazole 1.00Diclofenace sodium 1.00 Lidocaine base 2.00 Terbinafine HCl 1.00 Totalproduct: 100.00 100.00 100.00 100.00 100.00 Propellant: n-butane 20.0020.00 20.00 20.00 20.00 Results Shakability yes yes yes Yes yes Foamquality Good Good+ Good+ Good+ Good3c. Stock Emulsion with Zinc Oxide+API's

24 25 26 27 28 Ingredient w/w % w/w % w/w % w/w % w/w % Stock PFF 99.8895.00 85.00 95.00 99.75 Betamethasone 17 0.12 valerate micronizedAcyclovir 5.00 Azelaic acid 15.00 Caffeine 5.00 Miconazole nitrate 0.25Total product: 100.00 100.00 100.00 100.00 100.00 Propellant: n-butane20.00 20.00 20.00 20.00 20.00 Results Shakability yes yes yes yes yesFoam quality Good+ Good+ Good Good+ Good+

1. A non-aqueous, non-alcoholic foamable composition comprising: afoamable carrier and at least one liquefied or compressed gaspropellant, wherein the foamable carrier comprises: (1) a petrolatum ormixtures thereof at a concentration of about 25% to about 95% by weight;(2) a solvent substantially miscible in the petrolatum at aconcentration of about 0% to about 70% by weight; (3) at least one foamagent selected from the group consisting of a surfactant, a surfactantsystem, a foam adjuvant and combinations thereof; at a concentration ofabout 0.1% to about 20% by weight; wherein, in the absence of thesolvent, the petrolatum is present in the foamable carrier at aconcentration of at least about 50% by weight; wherein, in the presenceof the solvent: (i) the petrolatum is present in the foamable carrier ata concentration of at least about 25% by weight and the solvent andpetrolatum are together present in the foamable carrier at aconcentration of least about 55% by weight; or (ii) the amount ofpetrolatum is about the same as or in excess of the solvent and,together, the solvent and petrolatum are present in the foamable carrierat a concentration of at least about 80%; wherein the ratio of thefoamable carrier to the propellant is 100:10 to 100:35; wherein thecomposition is substantially free of silicone; and wherein thecomposition is stored in an aerosol container and upon release expandsto form a breakable foam.
 2. The composition of claim 1 wherein thecarrier further comprises at least one active pharmaceutical agent. 3.The composition of claim 2, wherein the composition is flowable orflowable to a degree and or is shakable or substantially so when storedin an aerosol container and upon release expands to form a breakablefoam having no substantial or sustained cooling affect and having a foamhardness in the range of about 5 g to about 100 g.
 4. The composition ofclaim 3, wherein the solvent is hydrophobic and is selected from thegroup consisting of an unctuous additive, an oil, a therapeutic oil, aPPG alkyl ether, or a combination thereof.
 5. The composition of claim 4wherein the solvent is PPG15 stearyl ether.
 6. The composition of claim4 wherein the solvent is a light mineral oil.
 7. The composition ofclaim 4 wherein the solvent is a combination of an oil or therapeuticoil and a PPG alkyl ether.
 8. The composition of claim 4 wherein thecarrier further comprises at least one additional solvent selected fromthe group consisting of a hydrophobic solvent, a polar solvent, apenetrating agent, polyethylene glycol (PEG), isosorbide derivatives,dimethyl isosorbide, propylene gycol (PG), hexylene glycol and glycerin,diethylene glycol monoethyl ether, a liquid polyethylene glycol,glycofurol, tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO,a pyrrolidone, N-methylpyrrolidones, N-Methyl-2-pyrrolidone,1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-typesurfactant, an alpha hydroxy acid, lactic acid and glycolic acid,hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol(transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol,mannitol, oligosaccharides, monooleate of ethoxylated glycerides havingabout 8 to 10 ethylene oxide units, and cyclodextrins, esters, ethylpropionate, tributylcitrate, acetyl triethylcitrate, acetyl tributylcitrate, triethylcitrate, ethyl butyrate, propylene glycol monoacetate,propylene glycol diacetate, epsilon-caprolactone and isomers thereof,delta-valerolactone and isomers thereof, beta-butyrolactone and isomersthereof dimethyl acetamide, and monooctanoin.
 9. The composition ofclaim 1 wherein the carrier can hold one or more active agents at aconcentration of up to about 33% by weight and still produce a goodquality stable breakable foam.
 10. The composition of claim 1 whereinthe carrier has a relatively high viscosity from about 12,000 CP toabout 500,000 CP.
 11. The composition of claim 4 wherein the propellantdissolves in the composition.
 12. The composition of claim 11 whereinthe propellant is selected from the group consisting of a propellantcomprising n-butane; a propellant comprising a mixture of n-butane,isobutene and propane and a propellant comprising a hydrofluorocarbon.13. The composition of claim 1 wherein the surfactant or surfactantsystem is selected from the group consisting of: a polysorbate;polyoxyethylene (20) sorbitan monostearate; sorbitan monooleate;polyoxyethylene (20) sorbitan monooleate; sorbitan laurate; apolyoxyethylene fatty acid ester; Myrj 45, Myrj 49, Myrj 52 and Myrj 59;a polyoxyethylene alkylyl ether; polyoxyethylene cetyl ether;polyoxyethylene palmityl ether; polyethylene oxide hexadecyl ether;polyethylene glycol cetyl ether; brij 38, brij 52, brij 56 and brij W1;behenyl alcohol; a sucrose ester; a partial ester of sorbitol; sorbitanmonolaurate; sorbitan monolaurate a monoglyceride; a diglyceride;isoceteth-20; ceteth 20 steareth 2; steareth 20; steareth 21; glycerylmonostearate; glucose methyl stearate; methyl glucose sesquistearate;Span 20; Span 80; Tween 20; Tween
 80. a mono, di or tri fatty acidsucrose ester; laureth-4; glyceryl stearate and PEG-100 stearate;ceteareth-6 and stearyl alcohol; myrj 52; poyglyceryl 10 laurate; POE(2) cetyl ether; cetearyl glucoside and cetyryl alcohol; methyl glucosesesquistearate; span 60; sucrose stearic acid esters; sorbitan stearateand sucrose cocoate; Peg 40 stearate; isosteareth 20; a polymericemulsifier, particularly Permulen (TRI or TR2); liquid crystal systems,particularly Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) andMontanov (68) or wherein the surfactant or surfactant system is acombination of at least two surfactants selected from the groupconsisting of combinations of: polyoxyethylene alkyl ethers,particularly Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 20;Steareth 2/Steareth 21 (Brij 72/BRIJ 721); Myrj 52/Myrj 59; combinationsof sucrose esters, particularly Surphope 1816/Surphope 1807;combinations of sorbitan esters, particularly Span 20/Span 80; Span20/Span 60; combinations of sucrose esters and sorbitan esters,particularly Surphope 1811 and Span 60; combinations of liquidpolysorbate detergents and PEG compounds, particularly Twin 80/PEG-40stearate/methyl glucaso sequistearate. glyceryl stearate and PEG-100stearate; ceteareth-6 and stearyl alcohol; cetearyl glucoside andcetyryl alcohol; sorbitan stearate and sucrose cocoate; and polysorbate80 and PEG-40 stearate.
 14. The composition of claim 1 wherein the foamadjuvant is selected from one or more of the group consisting of cetylalcohol, stearyl alcohol, myristyl alcohol, oleyl alcohol, behenylalcohol, and cetostearyl alcohol.
 15. The composition of claim 1 whereinthe petrolatum is substantially free of wax crystals.
 16. Thecomposition of claim 1 wherein the petrolatum is a mixture of a lowmelting point petrolatum and a higher melting point petrolatum.
 17. Thecomposition of claim 2 wherein the carrier further comprises at leastone modulating agent selected from the group consisting of a pHadjuster, a buffering agent, a chelator, an antioxidant and anantionisation agent.
 18. The composition of claim 2 wherein the carrierfurther comprises a stabilizing agent or preservative.
 19. Thecomposition of claim 1 wherein the carrier further comprises a polymericagent wherein the polymeric agent is 0.01% to 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent.
 20. Thecomposition of claim 2 wherein the carrier further comprises a polymericagent wherein the polymeric agent is 0.01% to 5% by weight and isselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent.
 21. Thecomposition of claim 2, wherein the foam resulting from the foamablecomposition demonstrates at least eighteen of the following properties:x) a foam quality of 5-6; y) a color of white to off-white; or ayellowish color: z) no odor or faint odor; or substantially masked odor;aa) a foam quality of 5-6 after one freeze-thaw cycle; bb) a foamquality of 5-6 after two freeze-thaw cycles; cc) a foam quality of 5-6after three freeze-thaw cycles; dd) a foam quality of 5-6 after fourfreeze-thaw cycles; ee) a foam quality of 5-6 after about 3 weeks'storage at 30° C.; ff) a foam quality of 5-6 after about 3 weeks'storage at 40° C.; gg) a foam quality of 5-6 after about 3 months'storage at 30° C.; hh) a foam quality of 5-6 after about 3 months'storage at 40° C.; ii) a collapse time of more than 50 seconds; jj) acollapse time of more than 120 seconds; kk) a collapse time of more than180 seconds; ll) a collapse time of more than 300 seconds; mm) a foamhardness in the range of about 5 g to about 100 g; nn) a foam hardnessin the range of about 15 g to about 55 g; oo) a foam hardness in therange of about 30 g to about 85 g; pp) a density of less than 0.5 g; qq)a density of less than 0.3 g; rr) a density of less than 0.2 g; ss) afoam corneometer value of at least 50 after washing a formulationapplied to the skin; and tt) an average focus group score of 60 or more22. The composition of claim 21, wherein the foam demonstrates all ofsaid properties.
 23. A non-aqueous, non-alcoholic foamable carriercomposition comprising: a foamable carrier and at least one liquefied orcompressed gas propellant, wherein the foamable carrier comprises: (1) apetrolatum or mixtures thereof at a concentration of about 50% to about95% by weight; (2) a solvent substantially miscible in the petrolatum ata concentration of about 0% to about 45% by weight; (3) at least onefoam agent selected from the group consisting of a surfactant, asurfactant system; a foam adjuvant and combinations thereof at aconcentration of about 0.1% to about 20% by weight; and (4) an effectiveamount of an active pharmaceutical agent; wherein the ratio of thefoamable carrier to the propellant ranges from about 100:10 to about100:35; wherein the composition is substantially free of silicone; andwherein the composition is resistant to centrifugation at 1000 rpm forabout 10 minutes; wherein the composition is flowable or flowable to adegree and or is shakable or substantially so when stored in an aerosolcontainer and upon release expands to form a breakable foam having nosubstantial or sustained cooling affect and having a foam hardness inthe range of about 5 g to about 100 g.
 24. The composition of claim 23wherein the carrier further comprises at least one solvent selected fromthe group consisting of a hydrophilic solvent, a hydrophobic solvent, apolar solvent, and a penetrating agent.
 25. A kit comprising a dualchamber device or dual dispenser head, a first canister comprising afirst foamable composition according to claim 3 comprising a firstactive pharmaceutical ingredient and a second canister comprising asecond foamable composition according to claim 3 comprising a secondactive pharmaceutical ingredient, wherein each canister is connectableto the said device or head.
 26. The kit of claim 25, wherein the firstactive pharmaceutical ingredient is a steroid and the second activepharmaceutical ingredient is a vitamin D derivative.
 27. A method oftreating, alleviating or preventing a disorder of a mammalian subject inneed thereof, comprising administering a therapeutically effectiveamount of a foam produced from the composition of claim 3 to anafflicted target site of said mammalian subject.
 28. A method oftreating, alleviating or preventing nappy rash of a mammalian subject inneed thereof, comprising administering a therapeutically effectiveamount of a foam produced from the compositions of claim 23 to anafflicted target site of said mammalian subject.
 29. The composition ofclaim 4 wherein the hydrophobic solvent is selected from the groupconsisting of: 1 a high-melting point hydrocarbon; 2 a liquid oiloriginating from vegetable, marine or animal sources; 3 an oil selectedfrom the group consisting of (1) a saturated oil; (2) an unsaturatedoil; and (3) a polyunsaturated oil; 4 an oil selected from the groupconsisting of olive oil, corn oil, soybean oil, canola oil, cottonseedoil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigiumaromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil,flaxseed oil, wheat germ oil and evening primrose oil; 5 anpoly-unsaturated fatty acid selected from the group consisting of (1) anomega-3 fatty acid and (2) an omega-6 fatty acid; 6 an poly-unsaturatedfatty acid selected from the group consisting of linoleic acid,linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA)and docosahexaenoic acid (DHA); 7 a therapeutically active oil; 8 anessential oil; 9 an oil derived from a plant selected from the groupconsisting of anise, basil, bergemont, camphor, cardamom, carrot,canola, cassia, catnip, cedarwood, citronella, clove, cypress,eucalyptus, frankincense, garlic, ginger, grapefruit, hyssop, jasmine,jojova, lavender, lavandin, lemon, lime, mandarin, marjoram, myrrh,neroli, nutmeg, orange, peppermint, petitgrain, rosemary, rosehip, sage,spearmint, star anise, tea tree, tangerine, thyme vanilla, verbena andwhite clover; 10 a silicone oil; 11 an oil selected from the groupconsisting of a polyalkyl siloxane, a polyaryl siloxane, a polyalkylarylsiloxane, a polyether siloxane copolymer, a polydimethylsiloxane and apoly(dimethylsiloxane)-(diphenyl-siloxane) copolymer; 12 a hydrophobicemollient; and 13 an oil selected from the group consisting of isopropylmyristate, isopropyl palmitate, isopropyl isostearate, diisopropyladipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate,cetyl lactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate,tocopheryl linoleate, wheat germ glycerides, arachidyl propionate,myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyllanolate, pentaerythrityl tetrastearate, neopentylglycoldicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate,myristyl myristate, octyl dodecanol, sucrose esters of fatty acids andoctyl hydroxystearate.
 30. The composition of claim 3, wherein theactive agent is selected from the group consisting of an anti-infectiveagent, an antibiotic agent, an antibacterial agent, an antifungal agent,an antiviral agent, an antiparasitic agent, a steroidalanti-inflammatory agent, a nonsteroidal anti-inflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, a steroid, a vasoactive agent, a vasoconstructor, avasodilator, vitamin A, a vitamin A derivative, a retinoid, vitamin B, avitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, avitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, avitamin F derivative, vitamin K, a vitamin K derivative, a wound healingagent, a burn healing agent, a disinfectant, an anesthetic, anantiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid,a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen,an immunogenic substance, a haptene, an oxidizing agent, an antioxidant,a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaricacid, an insectoside, a retinoid, an antiproliferative agent, ananticancer agent, a photodynamic therapy agent, an anti-wrinkle agent, aradical scavenger, a metal oxide (e.g., titanium dioxide, zinc oxide,zirconium oxide, iron oxide), silicone oxide, talc, an anti-acne agent,a skin whitening agent, a self tanning agent, an anti-cellulite agent, askin protective agent, a masking agent, an anti-wart agent, a refattingagent, a lubricating agent and mixtures thereof at any proportion orwherein the active agent is selected from the group consisting ofacyclovir, azelaic acid, allantoin, ammonium lactate, benzoyl peroxide,caffeine, calcipotriol, calcitriol, nicotinamide, ciclopirox olamine,clindamycin hydrochloride, clindamycin phosphate, clindamycin palmitatehydrochloride, coal tar, cyanocobalamine, diclofenac sodium, gentamycinsulphate, lactic acid, glycyrrhizinic acid, map (magnesium ascorbylphosphate), minoxidil, mupirocin, salicylic acid, terbinafine, urea,fusidic acid, a hydrocortisone, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, a clobetasol, a halobetasol, abatamethsone; halobetasol and clobetasol-17-propionate or 17-butyrate;ketoconazole, lidocaine hydrochloride, metronidazole, tetracycline,tetracycline hydrochloride, meclocycline sulfosalicylate, resorcinol,chloramphenicol, erythromycin, acriflavinium monochloride, ethacridinelactate, dibrompropamidine isetionate, chlorhexidine acetate,chlorhexidine gluconate, chlorhexidine hydrochloride, hexamidineisetionate, phenol, povidone-iodine, dequalinium chloride,hydroxyquinoline sulfate, potassium hydroxyquinoline sulphate,benzalkonium chloride, cetrimonium bromide, cetylpyridinium chloride,cetrimide, phenylmercuric acetate, phenylmercuric borate, mercuricchloride, silver nitrate, potassium permanganate, tosylchloramidesodium, prednisolone sodium phosphate, betamethasone sodium phosphate,betamethasone 17-valerate, betamethasone diproprionate, demeclocycline,demeclocycline hydrochloride, chlortetracycline hydrochloride,oxytetracycline hydrochloride, neomycin sulfate, bacitracin zinc,gentamicin sulphate, amikacin, amikacin sulphate, sulfathiazole sodium,mafenide acetate, idoxuridine, fumaric acid, mepyramine maleate,tripelennamine hydrochloride, promethazine hydrochloride, dimetindenemaleate, diphenhydramine hydrochloride, cinchocaine hydrochloride,oxybuprocaine hydrochloride, benzocaine, tetracaine hydrochloride,pramoxine hydrochloride, panthenol, dexpanthenol, calcium pantothenate,hyaluronic acid, trypsin, aminobenzoic acid, methylrosaniliniumchloride, sodium butyl hydroxybenzoate, sodium ethyl hydroxybenzoate,sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate,flucytosine and fluconazole.
 31. The composition of claim 30 wherein theactive agent is selected from the group consisting of a nonsteroidalanti-inflammatory drug, an immunosuppressive agent, an immunomodulator,an immunoregulating agent, a hormonal agent, a steroid, a steroidalanti-inflammatory agent, vitamin A, a vitamin A derivative, vitamin Dand a vitamin D derivative.
 32. The composition of claim 30 wherein theactive agent is calcipotriol or calcitriol.
 33. The composition of claim31 wherein the active agent is a steroid selected from the groupconsisting of betamethasone diproprionate, a clobetasol, a halobetasol,or derivatives thereof.
 34. The composition of claim 33 wherein theactive agent is a combination of betamethasone diproprionate andcalcipotriol.
 35. The composition of claim 2, wherein the active agentcomprises an extract or tincture comprising one or more beneficialagents selected from the group consisting of proteins, polypeptides,sugars, hyularonic acid herbal extracts and coal tar.
 36. A compositionof claim 23 wherein the composition provides at least two of thefollowing traits: a) increased solubility of the active agent; b)increased delivery of the active agent; c) enhanced skin barrier buildup; d) increased penetration of the active agent whilst replenishing theskin; or e) prolonging the delivery of the active agent whilstreplenishing the skin.
 37. A composition of claim 23 wherein thecomposition provides at least two of the following traits: a) thecomposition is able to at least partially solubilize the active agent;b) the composition is able to substantially solubilize the active agent;c) the active agent is at least partially soluble in petrolatum ormixtures thereof; d) the active agent is at least partially soluble in asolvent substantially miscible in petrolatum or mixtures thereof; e) theactive agent is at least partially soluble in a hydrophilic solvent; f)the active agent is at least partially soluble in an oil; g) the activeagent is at least partially soluble in a PPG alkyl ether; or h) theactive agent is insoluble or slightly soluble and is distributeduniformly in the composition.
 38. The compositions of claim 19 whereinthe polymeric agent selected from the group consisting of ASOS, an alkyllactate, C-12 to C-15 alkyl lactate, a cellulose, carboxymethylcellulose sodium, microcrystalline cellulose, methocel and xantham gum.39. The compositions of claim 20 wherein the polymeric agent selectedfrom the group consisting of ASOS, an alkyl lactate, C-12 to C-15 alkyllactate, a cellulose, carboxymethyl cellulose sodium, microcrystallinecellulose, methocel and xantham gum.
 40. A low water content,non-alcoholic foamable composition comprising: a foamable carrier and atleast one liquefied or compressed gas propellant, wherein the foamablecarrier comprises: (1) a petrolatum or mixtures thereof at aconcentration of about 25% to about 95% by weight; (2) a solventsubstantially miscible in the petrolatum at a concentration of 0% toabout 70% by weight; (3) at least one foam agent selected from the groupconsisting of a surfactant, a surfactant system, a foam adjuvant andcombinations thereof; at a concentration of about 0.1% to about 20% byweight; and (4) water at a concentration of up to about 26% by weightwherein, in the absence of the solvent, the petrolatum is present in thefoamable carrier at a concentration of at least about 50% by weight;wherein, in the presence of the solvent: (i) the petrolatum is presentin the foamable carrier at a concentration of at least about 25% byweight and the solvent and petrolatum are together present in thefoamable carrier at a concentration of least about 55% by weight; or(ii) the amount of petrolatum is about the same as or in excess of thesolvent and, together, the solvent and petrolatum are present in thefoamable carrier at a concentration of at least about 80%; wherein theratio of the foamable carrier to the propellant ranges from about 100:10to about 100:35; wherein the composition is substantially free ofsilicone; and wherein the composition is stored in an aerosol containerand upon release expands to form a breakable foam.
 41. A low watercontent, non-alcoholic foamable carrier composition comprising: afoamable carrier and at least one liquefied or compressed gaspropellant, wherein the foamable carrier comprises: (1) a petrolatum ormixtures thereof at a concentration of about 50% to about 95% by weight;(2) a solvent substantially miscible in the petrolatum at aconcentration of about 0% to about 45% by weight; (3) at least one foamagent selected from the group consisting of a surfactant, a surfactantsystem; a foam adjuvant and combinations thereof at a concentration ofabout 0.1% to about 20% by weight; and (4) an effective amount of anactive pharmaceutical agent; wherein the solvent is water and is presentin the carrier at a concentration of about 0.1% to about 26% by weight;wherein the ratio of the foamable carrier to the propellant ranges fromabout 100:10 to about 100:35; wherein the composition is substantiallyfree of silicone; and wherein the composition is resistant tocentrifugation at 1000 rpm for about 10 minutes; wherein the compositionis flowable or flowable to a degree and or is shakable or substantiallyso when stored in an aerosol container and upon release expands to forma breakable foam having no substantial or sustained cooling affect andhaving a foam hardness in the range of about 5 g to about 100 g.